Michael Mayersohn

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• Mayersohn, M. (2014). Predicting Drug Hemodialysis: Unbound Apparent Volume of Distribution (Vu) and Relationship to ClogP. International Journal of Pharmacology and Pharmaceutical Sciences, 1(4), 322-326.
• Mayersohn, M. (2011). Letter to the Editor. Current Therapeutic Research - Clinical and Experimental, 72(3), 138-139.
• Tang, H., & Mayersohn, M. (2011). Controversies in allometric scaling for predicting human drug clearance: An historical problem and reflections on what works and what does not. Current Topics in Medicinal Chemistry, 11(4), 340-350.
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  PMID: 21320063;Abstract: This review focuses on a discussion of the controversies in allometric scaling (AS) for predicting human clearance from a mathematical and statistical perspective. First, a history of allometric scaling in comparative biology and its use in pharmacokinetics are reviewed. It is shown that the application of AS in predicting human clearance values based on a limited number of animal species (typically, 3 or 4) contains fundamental statistical errors from when AS was first introduced from comparative biology. Second, the mathematical nature of various allometrically-based methods is revealed and the soundness of these methods is assessed. It is demonstrated that any of these methods, which incorporate a correction factor in a traditional allometric approach (varying-exponent allometry), not only reduces the statistical power of the allometric analysis, but are also incorrect with regard to aspects of biology. Finally, it is concluded that allometry remains a valuable tool for predicting human clearance, and should be applied in the context of a fixed exponent. However, fixed-exponent allometry does not provide satisfactory accuracy in predicting human clearance, since it is not able to capture the biological differences among species. Therefore, it is recommended that the overall effort in predicting human pharmacokinetics should be directed to the collection and generation of reliable data (both in vitro and in vivo) along with a better understanding of the DMPK properties of the chemical entity. © 2011 Bentham Science Publishers Ltd.
• Tang, H., Hussain, A., Leal, M., Fluhler, E., & Mayersohn, M. (2011). Controversy in the allometric application of fixed- versus varying-exponent models: A statistical and mathematical perspective. Journal of Pharmaceutical Sciences, 100(2), 402-410.
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  PMID: 20862773;Abstract: This commentary is a reply to a recent article by Mahmood commenting on the authors' article on the use of fixed-exponent allometry in predicting human clearance. The commentary discusses eight issues that are related to criticisms made in Mahmood's article and examines the controversies (fixed-exponent vs. varying-exponent allometry) from the perspective of statistics and mathematics. The key conclusion is that any allometric method, which is to establish a power function based on a limited number of animal species and to extrapolate the resulting power function to human values (varying-exponent allometry), is infused with fundamental statistical errors. © 2010 Wiley-Liss, Inc.
• Kuehl, P. J., Brenner, T., Jain, P. K., Karlage, K., Sepassi, K., Yang, G., Mayersohn, M., Yalkowsky, S. H., & Myrdal, P. B. (2008). Formulation and in vivo evaluation of chlorpropham (CIPC) oral formulations. Journal of Pharmaceutical Sciences, 97(12), 5222-5228.
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  PMID: 18383335;Abstract: The objective of these studies was to examine the in vivo performance of oral formulations of chlorpropham (CIPC). In order to develop a new oral formulation several different solubilization techniques were evaluated, namely: cosolvents, surfactants, and complexing agents. The solubilization data indicated that a conventional solution formulation was not plausible. Two self-emulsifying drug delivery systems (SEDDS) were developed and evaluated for stability. Both SEDDS formulations were found to be chemically stable. In vivo analysis of a SEDDS formulation, a suspension formulation and an intravenous bolus dose was conducted in F344 rats. Pharmacokinetic analysis of the formulation data indicated that the SEDDS formulation provided only marginally better oral bioavailability compared to a suspension formulation. While SEDDS formulations often result in greater bioavailability this was not observed for CIPC. In vivo analysis indicate that CIPC results in a situation where the dissolution rate of CIPC from the suspension is not rate limiting, rather the absorption rate in the GI tract is rate-limiting. This paradigm is the result of CIPCs low melting point and the relatively small particle size of the suspension which facilitate the dissolution in the GI tract. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association.
• Tang, H., & Mayersohn, M. (2007). Utility of the coefficient of determination (r²) in assessing the accuracy of interspecies allometric predictions: Illumination or illusion?. Drug Metabolism and Disposition, 35(12), 2139-2142.
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  PMID: 17761780;Abstract: The appropriateness of relying on the coefficient of determination (r 2) as a statistical metric for judging the predictability of human clearance (CL) based on interspecies animal data was assessed. An explicit mathematical expression was derived for r2 as a function of species body weight and the corresponding measured value of CL. The derived mathematical function demonstrated that r2 is numerically large in most instances. Simulations using random CL generated from a common combination of species of mouse, rat, and monkey resulted in an r2 of 0.75 as the minimum, and 0.95 and 0.98 at 50th and 75th percentiles, respectively, given that total CL values increase with increasing species body weight. Analysis of literature data also indicated that the prediction accuracy of human CL was not correlated with values of r2. Therefore, it is concluded that r 2 is a limited statistical measure when assessing allometric scaling for the purpose of predicting human CL. Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics.
• Tang, H., Hussain, A., Leal, M., Mayersohn, M., & Fluhler, E. (2007). Interspecies prediction of human drug clearance based on scaling data from one or two animal species. Drug Metabolism and Disposition, 35(10), 1886-1893.
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  PMID: 17646280;Abstract: A data-driven approach was adopted to derive new one- and two-species-based methods for predicting human drug clearance (CL) using CL data from rat, dog, or monkey (n = 102). The new one-species methods were developed as CL human/kg = 0.152 · CLrat/kg, CLhuman/kg = 0.410 · CLdog/kg, and CLhuman/kg = 0.407 · CLmonkey/kg, referred to as the rat, dog, and monkey methods, respectively. The coefficient of the monkey method (0.407) was similar to that of the monkey liver blood flow (LBF) method (0.467), whereas the coefficients of the rat method (0.152) and dog method (0.410) were considerably different from those of the LBF methods (rat, 0.247; dog, 0.700). The new rat and dog methods appeared to perform better than the corresponding LBF methods, whereas the monkey method and the monkey LBF method showed improved predictability compared with the rat and dog one-species-based methods and the allometrically based "rule of exponents" (ROE). The new two-species methods were developed as CLhuman = arat-dog · Whuman0.628 (referred to as rat-dog method) and CLhuman = a rat-monkey · Whuman0.650 (referred to as rat-monkey method), where arat-dog and arat-monkey are the coefficients obtained allometrically from the corresponding two species. The predictive performance of the two-species methods was comparable with that of the three-species-based ROE. Twenty-six Wyeth compounds having data from mouse, rat, dog, monkey, and human were used to test these methods. The results showed that the rat, dog, monkey, rat-dog, and rat-monkey methods provided improved predictions for the majority of the compounds compared with those for the ROE, suggesting that the use of three or more species in an allometrically based approach may not be necessary for the prediction of human exposure. Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics.
• Pak, Y., Stollberg-Zagar, K., & Mayersohn, M. (2006). A porcine model for fixed drug eruptions in humans: The case of antipyrine in the Yucatan micropig. Journal of Applied Toxicology, 26(1), 1-4.
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  PMID: 16307469;Abstract: To date, there is no acceptable animal model to investigate fixed drug eruptions (FDEs) in humans. We briefly report here observations suggesting that the Yucatan micropig may be a useful animal model for that purpose. During an investigation of antipyrine absorption and disposition, we observed the development of FDEs after intravenous administration of a 1 g dose. Our observations were consistent with those reported in several investigations of humans taking a single dose of antipyrine. To confirm these results, a naïve micropig was challenged. A male uncastrated Yucatan micropig (27.2 kg) was given a 1 g dose of antipyrine intravenously. After 30 days, this pig was rechallenged with the same intravenous dose of antipyrine (1 g). Blood samples were obtained to examine immunological endpoints. During the initial challenge, a fluid plaque (ca. 1-1.5 cm) appeared on the left hip of the pig ca. 6 h after dosing. After the rechallenge, inflamed pink patches were observed at the same sites where the blisters formed initially; however, no blisters re-formed. Changes of neutrophil, lymphocyte and eosinophil levels from baseline were noted 8 h after challenge. The micropig did not seem otherwise affected by the FDEs. These observations suggest that the Yucatan micropig, or swine in general, may be a useful animal model for detecting drugs that may cause FDEs in humans. Copyright © 2005 John Wiley & Sons, Ltd.
• Tang, H., & Mayersohn, M. (2006). A global examination of allometric scaling for predicting human drug clearance and the prediction of large vertical allometry. Journal of Pharmaceutical Sciences, 95(8), 1783-1799.
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  PMID: 16795013;Abstract: Allometrically scaled data sets (138 compounds) used for predicting human clearance were obtained from the literature. Our analyses of these data have led to four observations. (1) The current data do not provide strong evidence that systemic clearance (CLs, n = 102) is more predictable than apparent oral clearance (CLpo; n = 24), but caution needs to be applied because of potential CLpo prediction error caused by differences in bioavailability across species. (2) CLs of proteins (n = 10) can be more accurately predicted than that of non-protein chemicals (n = 102). (3) CLs is more predictable for compounds eliminated by renal or biliary excretion (n = 33) than by metabolism (n = 57). (4) CLs predictability for hepatically eliminated compounds followed the order: high CL (n = 11) > intermediate CL (n = 17) > low CL (n = 29). All examples of large vertical allometry (% error of prediction greater than 1000%) occurred only when predicting human CLs of drugs having very low CL s. A qualitative analysis revealed the application of two potential rules for predicting the occurrence of large vertical allometry: (1) ratio of unbound fraction of drug in plasma (fu) between rats and humans greater than 5; (2) C logP greater than 2. Metabolic elimination could also serve as an additional indicator for expecting large vertical allometry. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association.
• Tang, H., & Mayersohn, M. (2006). On the observed large interspecies overprediction of human clearance ("vertical allometry") of UCN-01: Further support for a proposed model based on plasma protein binding. Journal of Clinical Pharmacology, 46(4), 398-400.
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  PMID: 16554445;Abstract: The prediction of a human clearance (CL) value for UCN-01, an extreme example of vertical allometry (a large overprediction by allomettic scaling), was examined using commonly used simple allometry and the "rule of exponents," as well as a newly proposed model, which quantitatively incorporates plasma protein-binding information from rats and humans. Simple allometry and the rule of exponents were shown to overpredict the human CL value of UCN-01 by about 5000- and 1750-fold, respectively. The new model incorporating the ratio of fraction unbound between rats and humans improved the prediction by about 20-fold compared to the rule of exponents. The model is expected to improve if a more accurate measurement of the unbound fraction in human plasma is obtained. The prediction of volume distribution for UCN-01 by allometric scaling was also shown to be dependent on the difference of fraction unbound between animal species and humans. In summary, plasma protein binding has been demonstrated to be an important measure for interspecies scaling of pharmacokinetics. ©2006 the American College of Clinical Pharmacology.
• Tang, H., & Mayersohn, M. (2006). Response to comments on "A mathematical description of the functionality of correction factors used in allometry for predicting human drug clearance" [3]. Drug Metabolism and Disposition, 34(3), 510-511.
• Lund, B., Seifert, S. A., & Mayersohn, M. (2005). Efficacy of sustained low-efficiency dialysis in the treatment of salicylate toxicity. Nephrology Dialysis Transplantation, 20(7), 1483-1484.
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  PMID: 15797887;
• Tang, H., & Mayersohn, M. (2005). A mathematical description of the functionality of correction factors used in allometry for predicting human drug clearance. Drug Metabolism and Disposition, 33(9), 1294-1296.
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  PMID: 15919851;Abstract: The functionality of the correction factors, maximum life-span potential (MLP), and brain weight (BrW) used in allometry is mathematically described. Correction by MLP or BrW is equivalent to a multiplication of some constants by the predicted values in humans from simple allometry, but they have no relationship to measured pharmacokinetic parameters in the animal species. The values of these constants (FMLP or FBrW) were calculated for some commonly used combinations of animal species. For all combinations of animal species, the value of FBrW is always greater than that of FMLP with a fold-increase of about 1.3 to 1.9. Different combinations of species give different values of FBrW and FMLP. In addition, the role of correction factors (MLP and BrW) or the "rule of exponents" (ROE) was evaluated. An intrinsic defect in using correction factors or ROE was revealed; different study designs will produce significantly different prediction results. However, ROE may still serve as a useful practical approach in predicting human CL since it was derived from real observations and has been applied to many examples. Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics.
• Tang, H., & Mayersohn, M. (2005). A novel model for prediction of human drug clearance by allometric scaling. Drug Metabolism and Disposition, 33(9), 1297-1303.
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  PMID: 15958605;Abstract: Sixty-one sets of clearance (CL) values in animal species were allometrically scaled for predicting human clearance. Unbound fractions (f u) of drug in plasma in rats and humans were obtained from the literature. A model was developed to predict human CL: CL = 33.35 ml/min x (a/Rfu)0.770, where Rfu is the fu ratio between rats and humans and a is the coefficient obtained from allometric scaling. The new model was compared with simple allometric scaling and the "rule of exponents" (ROE). Results indicated that the new model provided better predictability for human values of CL than did ROE. It is especially significant that for the first time the proposed model improves the prediction of CL for drugs illustrating large vertical allometry. Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics.
• Tang, H., & Mayersohn, M. (2005). Accuracy of allometrically predicted pharmacokinetic parameters in humans: Role of species selection. Drug Metabolism and Disposition, 33(9), 1288-1293.
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  PMID: 15919852;Abstract: A general equation was derived, which directly describes the mathematical relationship between the allometrically predicted pharmacokinetic (PK) parameters in humans and the body weights of animal species (along with their corresponding measured PK parameters). It was shown, with use of the derived equation, that the predicted values in humans, based on combinations of animal species commonly used in allometry, are heavily dependent on certain species, for example, the dog. In contrast, parameter values from the rat made no contribution to the predicted human values, as long as the rat was not the smallest species used. Monte Carlo simulations were further performed to examine the species or weight dependence. The cost-effective combinations of animal species, in terms of number and species type, were theoretically examined through simulations. Finally, literature data demonstrated the species or weight dependence predicted from the equation and as illustrated through the Monte Carlo simulations. Appreciation of this species or weight dependence should guide researchers in selecting animal species and designing optimal experiments in the application of allometric scaling. Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics.
• Martin, D., Valdez, J., Boren, J., & Mayersohn, M. (2004). Dermal absorption of camphor, menthol, and methyl salicylate in humans. Journal of Clinical Pharmacology, 44(10), 1151-1157.
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  PMID: 15342616;Abstract: Camphor, menthol, and methyl salicylate occur in numerous over-the-counter products. Although extensively used, there have been no estimates of human exposure following administration via dermal application. Furthermore, there is little information about the pharmacokinetics of those compounds. The authors report the plasma concentrations of the intact compounds as a function of dose following dermal patch application. Three groups of 8 subjects (4 male, 4 female) applied a different number of commercial patches (2, 4, or 8) to the skin for 8 hours. Plasma samples were assayed using sensitive and selective gas-chromatographic methods. For the 8-patch group, the average maximum plasma concentrations (Cmax ± SD) were 41.0 ±5.8 ng/mL, 31.9 ± 8.8 ng/mL, and 29.5 ± 10.5 ng/mL for camphor, menthol, and methyl salicylate, respectively. The corresponding values for the 4-patch group were 26.8 ± 7.2 ng/mL, 19.0 ±5.4 ng/mL, and 16.8 ± 6.8 ng/mL. The harmonic mean terminal half-lives were 5.6 ± 1.3 hours, 4.7 ± 1.6 hours, and 3.0 ± 1.2 hours for camphor, menthol, and methyl salicylate, respectively. The 2-patch group had measurable but low plasma concentrations of each compound. Low-dose dermal application for an extended time results in low plasma concentrations of all 3 compounds. Four and 8 patches, when applied for 8 hours, gave measurable and nearly proportional plasma concentrations. Although unable to determine the absolute dermal bioavailability of these compounds, there appears to be relatively low systemic exposure to these potentially toxic compounds, even when an unrealistically large number of patches are applied for an unusually long time.
• Tang, H., Pak, Y., & Mayersohn, M. (2004). Protein expression pattern of P-glycoprotein along the gastrointestinal tract of the Yucatan micropig. Journal of Biochemical and Molecular Toxicology, 18(1), 18-22.
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  PMID: 14994275;Abstract: The purpose of this study is to characterize the distribution pattern of P-gp protein levels along the entire GI tract in the Yucatan micropig, which is being developed as a model for human drug bioavailability. Small and large intestines were freshly obtained and divided into about 37 segments and 10 segments, respectively (ca., 1 foot/segment). Epithelial cells from the small intestine were obtained by an elution method; whereas, a scraping method was applied to the large intestine. Total cellular protein was isolated from the epithelial cells. Western blot analysis using P-gp antibody showed that the amount of P-gp protein increased distally from the duodenum to the ileum over approximately a 10-fold range. P-gp protein in the large intestine was present at a higher level in the central portion, but the absolute amount was much less than what was found in the small intestine. © 2004 Wiley Periodicals, Inc.
• Pak, Y., Patek, R., & Mayersohn, M. (2003). Sensitive and rapid isocratic liquid chromatography method for the quantitation of curcumin in plasma. Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences, 796(2), 339-346.
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  PMID: 14581073;Abstract: An HPLC assay was developed using three methods of plasma sample preparation in order to quantitate curcumin, the main constituent in the herbal dietary supplement turmeric. Each method involves simple and rapid processing of samples (either an ethyl acetate or chloroform extraction) with resulting different quantitation limits for curcumin. The assay was developed in an effort to quantify extremely low curcumin plasma concentrations observed in preliminary in vivo studies. The most sensitive assay can reliably detect concentrations down to 2.5ng/ml. Plasma quantitation was precise and accurate based on both intra- and inter-day validations as indicated by low values for coefficients of variation and bias, respectively (≤15%). The analytical validation was reproducible between different analysts. The resulting analytical method couples desired sensitivity with the ease of an isocratic system. © 2003 Elsevier B.V. All rights reserved.
• Sanghvi, T., Nina, N. i., Mayersohn, M., & Yalkowsky, S. H. (2003). Predicting passive intestinal absorption using a single parameter. QSAR and Combinatorial Science, 22(2), 247-257.
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  Abstract: A model is proposed for the prediction of either high or low fraction absorbed for an orally administered, passively transported drug on the basis of a new absorption parameter, ∏. The model includes only two inputs: the octanol-water partition coefficient (Kow) and the dimensionless oversaturation number (OLumen). The latter is the ratio of the concentration of drug delivered to the gastro-intestinal (GI) fluid to the solubility of the drug in that environment. Thus, OLumen is equal to the dose-normalized solubility for suspensions and unity for solutions. The value of ∏ increases with an increase in Kow and a decrease in OLumen for suspensions, and is equal to Kow for solutions. The effectiveness of the model is validated using experimental human gastrointestinal absorption data for 98 compounds. About 88% of these drugs are correctly predicted to be either well absorbed or poorly absorbed based solely upon whether their ∏ value is greater than or less than unity. Thus, the use of a single absorption parameter, ∏ provides a simple means to estimate whether or not an orally administered drug undergoing passive transport will be absorbed efficiently. The advantage of this parameter is that it is based upon simple, easily measured (or calculated) physical chemical data. It is especially noteworthy that experimental measurement of in vitro membrane transport is not required. The model based on the new absorption parameter is shown to have wider applicability than current available models for predicting the fraction absorbed.
• Mayersohn, M. (2001). Measurement of disposition half-life, clearance, and residence times.. Current protocols in toxicology / editorial board, Mahin D. Maines (editor-in-chief) ... [et al.], Chapter 5, Unit5.3.
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  PMID: 20949436;Abstract: This unit provides an overview of the principles underlying the elimination process. Experimental design issues, methods of data analysis, and complications that may be encountered are discussed. A complete worked example is provided to exemplify the methods of analysis that are available.
• Kakkar, T., Pak, Y., & Mayersohn, M. (2000). Evaluation of a minimal experimental design for determination of enzyme kinetic parameters and inhibition mechanism. Journal of Pharmacology and Experimental Therapeutics, 293(3), 861-869.
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  PMID: 10869386;Abstract: The advent of combinatorial chemistry has led to a deluge of new chemical entities whose metabolic pathways need to be determined. A significant issue involves determination of the ability of new agents to inhibit the metabolism of existing drugs as well as its own susceptibility for altered metabolism. There is need to estimate the enzyme inhibition parameters and mechanism or mechanisms of inhibition with minimal experimental effort. We examined a minimal experimental design for obtaining reliable estimates of K(i) (and V(max) and K(m)). Simulations have been applied to a variety of experimental scenarios. The least experimentally demanding case involved three substrate concentrations, [S], for the control and one substrate-inhibitor pair, [S]-[I]. The control and inhibitor data (with 20% coefficient of variance random error) were simultaneously fit to the full nonlinear competitive inhibition equation [simultaneous nonlinear regression (SNLR)]. Excellent estimates of the correct kinetic parameters were obtained. This approach is clearly limited by the a prior assumption of mechanism. Further simulations determined whether SNLR would permit assessment of the inhibition mechanism (competitive or noncompetitive). The minimal design examined three [S] (control) and three [S]-[I] pairs. This design was successful in identifying the correct model for 98 of 100 data sets (20% coefficient of variance random error). SNLR analysis of metabolite formation rate versus [S] permits a dramatic reduction in experimental effort while providing reliable estimates of K(i), K(m), and V(max) along with an estimation of the mechanism of inhibition. The accuracy of the parameter estimates will be affected by the experimental variability of the system under investigation.
• Sinha, V., Brendel, K., & Mayersohn, M. (2000). A simplified isolated perfused rat liver apparatus: Characterization and measurement of extraction ratios of selected compounds. Life Sciences, 66(19), 1795-1804.
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  PMID: 10809177;Abstract: A simplified isolated perfused rat liver (IPRL) preparation has been developed and evaluated. The liver is briefly perfused in situ prior to being placed into a 37°C oven and suspended from a stand. This set-up takes about 5 min. A non-recirculatory or one-pass perfusion approach has been used. The performance of the apparatus was evaluated with use of three model compounds: antipyrine, lidocaine and ethanol. In addition, oxygen extraction was determined. The steady-state extraction ratio (ER) was determined for each compound (and oxygen) as a function of perfusate flow rate (15-35 ml/min) during sequential 45 min perfusion periods. Perfusion experiments lasted for up to 3 hr. The ERs (at 15 ml/min) of ethanol (0.65 ± 0.15), lidocaine (0.91 ± 0.01) and oxygen (0.65 ± 0.10) were dependent upon perfusate flow; whereas, antipyrine ER (0.07 ± 0.01) was independent of flow. The corresponding values for unbound intrinsic clearances (CL(u,int)) for antipyrine, ethanol, lidocaine and oxygen were: 1.6, 31.0, 158.0 and 27.5 ml/min, respectively. These findings are consistent with the known hepatic ER values for those compounds reported in the literature.
• Boxenbaum, H., Tannenbaum, S., Mayersohn, M., & Oleson, F. (1999). Pharmacokinetics tricks and traps: drug dosage adjustment in renal failure.. Journal of pharmacy & pharmaceutical sciences [electronic resource] : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques, 2(1), 2-4.
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  PMID: 10951656;
• H.J., J. P., Mayersohn, M., Adams, M. P., Reinhart, R. J., & Barrett, J. S. (1999). Moricizine bioavailability via simultaneous, dual, stable isotope administration: Bioequivalence implications. Journal of Clinical Pharmacology, 39(8), 817-825.
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  PMID: 10434234;Abstract: The relative bioavailability of a 200 mg film-coated tablet of [12C]moricizine·HCI in comparison to a 200 mg [13C6]moricizine·HCI oral solution was determined after simultaneous administration to 8 young healthy male subjects. Concentrations of [12C]moricizine·HCl and [13C6]moricizine·HCI were determined by thermospray liquid chromatography-mass spectrometry (LC-MS) using [2H11]moricizine·HCI as the internal standard. The mean absorption and disposition parameters of the tablet versus the solution were the following (% CV): maximum concentration, 0.83 (39%) versus 0.79 (39%) μg/mL; time of maximum concentration, 0.81 (40%) versus 0.65 (28%) hours; area under the concentration-time curve (AUC), 1.58 (39%) versus 1.49 (37%) μg·h/mL; apparent oral clearance, 150.7 (52%) versus 158.1 (50%) L/h; and t( 1/2 ), 1.9 (42%) versus 1.9 (42%) hours. The AUC for the tablet averaged 106% of the solution, which likely reflects a greater first-pass effect with the oral solution. Partitioning sources of variation confirmed the low (< 6%) intrasubject coefficient of variation (cv) afforded via the single-period, dual-isotope design. In contrast, a previous study using the conventional two-period crossover design determined the cvε about moricizine metrics to be in excess of 30%, resulting in classification of this drug as having highly variable absorption. The results of this studyfurther illustrate the benefits of dual, stable isotopes to assess bioavailability and bioequivalence. This paradigm results in a reduction in experimental time and subject inconvenience and lower costs in comparison with the standard crossover study. Perhaps most important is the improved statistical power for the evaluation of bioavailability or bioequivalence in the absence of period and sequence effects that confound the assessment of intrasubject variation in the standard crossover design. (C)1999 the American College of Clinical Pharmacology.
• Kakkar, T., Boxenbaum, H., & Mayersohn, M. (1999). Estimation of K(i) in a competitive enzyme-inhibition model: Comparisons among three methods of data analysis. Drug Metabolism and Disposition, 27(6), 756-762.
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  PMID: 10348808;Abstract: There are a variety of methods available to calculate the inhibition constant (K(i)) that characterizes substrate inhibition by a competitive inhibitor. Linearized versions of the Michaelis-Menten equation (e.g., Lineweaver-Burk, Dixon, etc.) are frequently used, but they often produce substantial errors in parameter estimation. This study was conducted to compare three methods of analysis for the estimation of K(i): simultaneous nonlinear regression (SNLR); nonsimultaneous, nonlinear regression, 'K(M,app)' method; and the Dixon method. Metabolite formation rates were simulated for a competitive inhibition model with random error (corresponding to 10% coefficient of variation). These rates were generated for a control (i.e., no inhibitor) and five inhibitor concentrations with six substrate concentrations per inhibitor and control. The K(M)/K(i) ratios ranged from less than 0.1 to greater than 600. A total of 3 data sets for each of three K(M)/K(i) ratios were generated (i.e., 108 rates/data set per K(M)/K(i) ratio). The mean inhibition and control data were fit simultaneously (SNLR method) using the full competitive enzyme-inhibition equation. In the K(M,app) method, the mean inhibition and control data were fit separately to the Michaelis-Menten equation. The SNLR approach was the most robust, fastest, and easiest to implement. The K(M,app) method gave good estimates of K(i) but was more time consuming. Both methods gave good recoveries of K(M) and V(MAX) values. The Dixon method gave widely ranging and inaccurate estimates of K(i). For reliable estimation of K(i) values, the SNLR method is preferred.
• Pieniaszek Jr., H. J., Davidson, A. F., Chaney, J. E., Shum, L., Robinson, C. A., & Mayersohn, M. (1999). Human moricizine metabolism. II. Quantification and pharmacokinetics of plasma and urinary metabolites. Xenobiotica, 29(9), 945-955.
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  PMID: 10548454;Abstract: 1. The metabolism of moricizine·HCl was studied in 12 male volunteers dosed with 250 mg (300 μCi) 14C-radiolabelled drug. 2. Moricizine was biotransformed to many metabolites in humans (at least 35 plasma and 51 urine metabolites). 3. Urine and faecal combined mean (range) recovery accounted for 90.2% (73.4-101.6%) of the administered radioactivity, with most of the recovered radioactivity present in faeces (mean 58.4%; range 45.6-64.7%). Mean (range) urinary recovery was 31.8% (26.2-36.9%), with < 1% of the dose recovered as intact moricizine, and no one metabolite accounting for > 2.5% of the dose. 4. Total radioactivity (TR) plasma t(1/2) was 85.2 h, while that for moricizine was 2.4 h. Mean half-lives for plasma metabolites ranged from 2.9 to 23.6 h. The largest portion (11%) of TR AUC (area under the plasma concentration-time curve) was attributed to 2-amino-10-glucuronophenothiazine. Each of the other metabolites accounted for less of the TR AUC than parent drug except for two unidentified peaks which had comparable areas (~ 5% of the total radioactivity area). 5. Two identified moricizine metabolites, 2-amino-10-(3-morpholinopropionyl) phenothiazine and ethyl [10-(3-aminopropionyl) phenothiazin-2-yl] carbamate, possess the structural characteristics proposed for class 1 anti-arrhythmic activity (pendant amine functionality) and have plasma half-lives 4-7-fold longer than moricizine.
• Valdez, J. S., Martin, D. K., & Mayersohn, M. (1999). Sensitive and selective gas chromatographic methods for the quantitation of camphor, menthol and methyl salicylate from human plasma. Journal of Chromatography B: Biomedical Sciences and Applications, 729(1-2), 163-171.
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  PMID: 10410939;Abstract: Analytical methods using gas chromatography-flame ionization detection (GC-FID) for the quantitation of camphor and menthol and GC-MS for the quantitation of methyl salicylate have been developed for measurement of low concentrations from human plasma. Anethole serves as the internal standard for camphor and menthol and ethyl salicylate serves as the internal standard for methyl salicylate. Plasma samples undergo multiple, sequential extractions with hexane in order to provide optimal recovery. For menthol and camphor, the extracting solvent is reduced in volume and directly injected onto a capillary column (Simplicity-WAX). Extracted methyl salicylate is derivatized with BSTFA prior to injection onto a capillary column (Simplicity-5). Between-day variation (% RSD) at 5 ng/ml varies from 6.2% for methyl salicylate to 13.5% for camphor. The limit of detection for each analyte is 1 ng/ml and the limit of quantitation is 5 ng/ml. These analytical methods have been used in a clinical study to assess exposure from dermally applied patches containing the three compounds. Copyright (C) 1999 Elsevier Science B.V.
• Bourland, J. A., Martin, D. K., & Mayersohn, M. (1998). In vitro transesterification of cocaethylene (ethylcocaine) in the presence of ethanol: Esterase-mediated ethyl ester exchange. Drug Metabolism and Disposition, 26(3), 203-206.
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  PMID: 9492381;Abstract: This study reports that cocaethylene undergoes an esterase-mediated ethyl ester exchange with ethanol, resulting in an increase in the apparent in vitro t( 1/4 ), compared with control conditions. Homogenized liver from male Sprague Dawley rats in pH 7.4 phosphate buffer was centrifuged at 9000g, and the resulting supernatant (S9) fraction was collected. Tubes containing the rat S9 fraction and 50 μM cocaethylene plus aqueous buffer (control), 50 mM ethanol, or 51.3 mM 2H6-ethanol were incubated at 37°C for 4 hr. Samples were collected from the incubation tubes at various times, extracted with a solid-phase extraction system, and assayed for cocaethylene and 2H5- cocaethylene by GC/MS. Concentration-time profiles were constructed and kinetic parameters were determined. The experiment was repeated in the presence of specific and nonspecific esterase inhibitors. Enzyme kinetic parameters were also determined. Cocaethylene underwent ethyl ester exchange, being converted to 2H6-cocaethylene in the presence of 2H6-ethanol. The average apparent in vitro t( 1/4 ) value for cocaethylene (13.0 ± 1.4 min) incubated with the S9 fraction and buffer only was increased ~5-fold (67.8 ± 0.3 min) in the presence of ethanol. Formation of 2H6-cocaethylene was totally blocked with the addition of bis-(p-nitrophenyl)phosphate but was unaffected by physostigmine. The intrinsic metabolite formation clearance of 2H6-cocaethylene from cocaethylene and 2H6-ethanol (1.92 ± 0.03 μl/min- mg protein) was several times greater than the corresponding value for cocaethylene formation from cocaine and ethanol (0.94 ± 0.01 μl/min-mg protein) or 2H6-ethanol (0.87 ± 0.04 μl/min-mg protein).
• Chow, H., Khor, S. P., Lee, H., & Mayersohn, M. (1998). A modified equilibrium dialysis technique for measuring plasma protein binding: Experimental evaluation with diazepam and nortriptyline. Pharmaceutical Research, 15(10), 1643-1646.
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  PMID: 9794511;
• Foster, B. S., Gilbert, D. D., Hutchaleelaha, A., & Mayersohn, M. (1998). Enantiomeric determination of amphetamine and methamphetamine in urine by precolumn derivatization with Marfey's reagent and HPLC. Journal of Analytical Toxicology, 22(4), 265-269.
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  PMID: 9681327;Abstract: An analytical method was developed for enantiomeric determination of amphetamine and methamphetamine in human urine. The enantiomers were isolated from urine by solid-phase extraction, and diastereomers were formed by derivatization with the chiral Marfey's reagent (1-fluoro-2,4-dinitrophenyl- 5-l-aniline amide). The diastereomers were separated by reversed-phase high- performance liquid chromatography in a water/methanol mobile phase and detected by absorbance spectrophotometry at 340 nm. Linear standard curves were obtained for all four enantiomers over a concentration range of 0.16- 1.00 mg/L in urine. The detection limit was 0.16 mg/L urine for each enantiomer, and the limit of quantitation was 0.40 mg/L. The urine of 10 decedents was analyzed by this method and by a previously published precolumn derivatization procedure using (-)-1-(9-fluorenyl)ethyl chloroformate (FLEC) as the derivatizing agent and fluorescence detection. Comparison of the results of the two methods by linear regression showed comparable results for both d-amphetamine and d-methamphetamine. Neither method detected the presence of the l-enantiomers in the urine samples.
• Kakkar, T., & Mayersohn, M. (1998). Simultaneous quantitative analysis of methyl salicylate, ethyl salicylate and salicylic acid from biological fluids using gas chromatography-mass spectrometry. Journal of Chromatography B: Biomedical Applications, 718(1), 69-75.
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  PMID: 9832362;Abstract: A gas chromatographic-mass spectrometric (GC-MS) assay was developed for the quantitative analysis of methyl salicylate (MeS), ethyl salicylate (ES) and salicylic acid (SA) from biological fluids. The method was validated from 100-μl rat liver homogenate preparations (5 mg/ml protein) in 70 mM KH2PO4 (pH 7.4) buffer and from 100 μl rat plasma. The samples were extracted with chloroform, derivatized with BSTFA and quantitated by GC-MS in the SIM mode. The standard curves ranged from 31 ng/ml to 800 or 1250 ng/ml. Relative standard deviations and bias were less than 11% in plasma and homogenate for all compounds except SA which evidenced greater variability. The assay was used in preliminary experiments to characterize the pharmacokinetics of MeS in rats. Copyright (C) 1998 Elsevier Science B.V.
• Mayersohn, M., & Tannenbaum, S. (1998). On reclaiming data from the literature: Literature data "R and R"(recovery and reanalysis). American Journal of Pharmaceutical Education, 62(4), 363-371.
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  Abstract: It is common practice to perform a literature review on a selected topic in order to accomplish one or more goals (e.g., preparation of a seminar, lecture, grant application, review paper, etc.). A critical analysis of the literature often requires recovering data from a publication. The latter can be a challenge when data are presented graphically, especially when non-uniform or non-linear (e.g., logarithmic) scales are used. The recovered data then provides a basis for reanalysis and reinterpretation. The purpose of this communication is to discuss methods available for recovering graphical data from the literature with emphasis on scanning and digitization procedures. Data from graphs in several publications have been recovered after scanning the graph into a file and using a software program which permits on-screen digitization. Only publications which had a tabular listing of the plotted values were examined in order to provide some estimate of the accuracy of the digitization process. Recovered values are accurate and rarely differ by more than about 2-3 percent from the correct (i.e., literature) value. Furthermore, the between-investigator range in the recovered values is small (based upon digitization by 11 investigators). The utility of data recovery is shown with a literature example. Data in one publication afforded the opportunity to extend the authors' original analysis to create a pharmacokinetic/pharmacodynamic model to describe cocaethylene (ethylcocaine) in the dog. We conclude that scanning of literature graphs followed by digitization, provides a means of accurately reclaiming data from the literature and offers a unique opportunity to reanalyze the data and, perhaps, to generate a different perspective.
• Troy, S. M., Rudolph, R., Mayersohn, M., & Chiang, S. T. (1998). The influence of cimetidine on the disposition kinetics of the antidepressant venlafaxine. Journal of Clinical Pharmacology, 38(5), 467-474.
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  PMID: 9602962;Abstract: The influence of cimetidine on the disposition pharmacokinetics of the antidepressant drug, venlafaxine, and its active metabolite, O- desmethylvenlafaxine, was examined in 18 healthy young men and women. The steady-state pharmacokinetic profiles of venlafaxine and O- desmethylvenlafaxine were evaluated during a 24-hour period after 5 days of treatment with venlafaxine (50 mg three times a day) and during a second 24- hour period after 5 days of combination treatment with venlafaxine (50 mg three times a day) and cimetidine (800 mg once a day). The apparent oral clearance of venlafaxine decreased significantly in the presence of cimetidine and the average steady-state plasma concentration of venlafaxine increased significantly in the presence of cimetidine, but there were no changes in the corresponding concentrations of the active metabolite. However, O-desmethylvenlafaxine exhibits pharmacologic activity that is approximately equimolar to that of venlafaxine, and the sum of venlafaxine plus O-desmethylvenlafaxine plasma concentrations was increased by an average of only 13%. Therefore, the effect of cimetidine coadministration is not expected to result in clinically important alterations in the response to venlafaxine in patients with depression. This may not be true, however, for patients with compromised hepatic metabolic function.
• Bourland, J. A., Martin, D. K., & Mayersohn, M. (1997). Carboxylesterase-mediated transesterification of meperidine (Demerol) and methylphenidate (Ritalin) in the presence of [²H₆]ethanol: Preliminary in vitro findings using a rat liver preparation. Journal of Pharmaceutical Sciences, 86(12), 1494-1496.
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  PMID: 9423167;
• Hutchaleelaha, A., & Mayersohn, M. (1997). p-hydroxymethamphetamine enantiomer pharmacokinetics and metabolism in rats: Absence of N-demethylation. Biopharmaceutics and Drug Disposition, 18(5), 423-432.
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  PMID: 9210980;Abstract: p-hydroxymethamphetamine (OHMAP) is one of the major metabolites of the widely abused drug methamphetamine (MAP). The demethylation of OHMAP to p- hydroxyamphetamine (OHAP) has been shown in vitro but has never been reported in vivo. The disposition kinetics as well as the metabolism of OHMAP was investigated employing a sensitive HPLC method which can separate the enantiomers of OHMAP and OHAP. Both conjugated and unconjugated forms of these compounds can bc quantitated. Male Sprague Dawley rats were given an iv bolus oF racemic OHMAP (20mgkg-1) and serum and urine samples were collected at selected times. The serum concentration time data for OH MAP enantiomers could be described by a biexponential equation. Tile clearance of D-OHMAP (93.5mL min-1 kg -1) was slightly, but statistically significantly, greater than that of the L-enantiomer (83.9mL min-1 kg-1). The steady-state volumes of distribution of L- and D-OHMAP were (mean±SD) 3.15±0.84 and 4.23±1.76L kg-1 respectively. No significant concentrations or amounts of OHAP enantiomers could he detected in any serum or urine sample. Rats excreted more unchanged L-OHMAP (34%) than D-OHMAP (29%). In contrast, more conjugated D-OHMAP (57%) was recovered compared to the conjugated L-OHMAP (52%). The results suggest that there is slight stereoselectivity in the disposition of OHMAP enantiomers. The N- demethylation product (OHAP) was not produced in vivo.
• Hutchaleelaha, A., Chow, H., & Mayersohn, M. (1997). Comparative pharmacokinetics and interspecies scaling of amphotericin B in several mammalian species. Journal of Pharmacy and Pharmacology, 49(2), 178-183.
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  PMID: 9055191;Abstract: This study employed several interspecies scaling methods, to evaluate the applicability of extrapolating to man, pharmacokinetic information obtained from animals for amphotericin B, an anti-fungal drug. Pharmacokinetic parameters from four animal species (mouse, rat, monkey and dog) and man were obtained from the literature or from analysis of data reported in the literature. The allometric relationships (obtained from four animal species) as a function of species body weight (W; kg) for systemic clearance per maximum life span potential (CL(S)/MLP), steady-state volume of distribution (V(SS)), apparent volume of distribution (V(β)) and volume of the central compartment (V(C)) were: 5691W1.096; 2.46W0.839; 3.08W0.948 and 1.07W0.965 respectively. The allometric relationships for half-life (h) and mean residence time (h) did not scale well with body weight. The prediction of pharmacokinetic parameters in man from the allometric equations do not always agree with those reported in the literature which are based upon a limited number of studies with few human subjects. The plasma concentration-time profiles from these animals were adjusted by normalizing the concentration with dose/W0.948, and re-plotted on different pharmacokinetic time scales. The syndesichrons plot produced an almost superimposable profile of adjusted concentrations as a function of adjusted time among the four species.
• Hutchaleelaha, A., Sukbuntherng, J., & Mayersohn, M. (1997). Simple apparatus for serial blood sampling in rodents permitting simultaneous measurement of locomotor activity as illustrated with cocaine. Journal of Pharmacological and Toxicological Methods, 37(1), 9-14.
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  PMID: 9086283;Abstract: A simple device has been developed for serial venous blood sampling which permits the simultaneous measurement of locomotor activity in the freely moving rat. The device can be easily constructed from routine laboratory material and it does not interfere with the light beams used to measure locomotor activity. The device, in conjunction with an activity cage, has been applied to the combined pharmacokinetic and pharmacodynamic modeling of cocaine. The relationship between the locomotor activity following a single short iv infusion of cocaine (5 mg/kg) and cocaine plasma concentrations can be adequately described by the Sigmoid-E(max) model. Further, the relationship between activity and time can be described by the same model coupled with an effect compartment. These results suggest the applicability of the device in facilitating pharmacokinetic/pharmacodynamic modeling of drugs that affect locomotor activity.
• Sauer, J., Bao, J., Smith, R. L., Kuester, R. K., Mayersohn, M., & Sipes, I. G. (1997). Absorption, disposition, and metabolism of trans-methyl styryl ketone in female B6C3F₁ mice. Drug Metabolism and Disposition, 25(10), 1184-1190.
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  PMID: 9321522;Abstract: trans-Methyl styryl ketone (MSK; trans-4-phenyl-3-buten-2-one) is a β- unsaturated ketone that has a wide range of uses in industry, as well as consumer products. MSK does not appear to be overtly toxic in animal models, however, it has been shown to be mutagenic in several in vitro assays after S-9 activation. In this study experiments were conducted to characterize MSK absorption, distribution, metabolism, and elimination after iv, oral, and topical administration to female B6C3F1 mice. After iv administration, [14C]MSK (20 mg/kg; 120 μCi/kg) was rapidly cleared from the blood as evidenced by the following pharmacokinetic values (mean ± SD): terminal disposition half-life (t 1/4 ), 7.98 ± 1.72 min; mean residence time, 5.6 ± 1.7 min; steady-state apparent volume of distribution (V88), 3.33 ± 0.75 liters/kg; and systemic body clearance (CL8), 0.53 ± 0.08 liters/min/kg. Within 48 hr, 92.4% of the dose was excreted in the urine and 3.5% in the laces. The major blood metabolites after iv administration were identified by GC-MS as the 4-phenyl-3-buten-2-ol (methyl styryl carbinol), 4-hydroxy-4- phenyl-2-butanone, and benzyl alcohol. After oral administration of [14C]MSK (200 mg/kg; 100 μCi/kg), 95% of the dosed radioactivity was recovered in the urine and 1.2% in the faces within 48 hr. Major urinary metabolites were identified by LC-MS/MS as N-phenylacetyl-l-glycine (35.1% of dose) and N-benzyl-L-glycine (19.1% of dose). Only a small amount of MSK was detected in the blood after oral administration (~0.73 μg/ml at 10 min), and [14C]-equivalents in the blood never exceeded 2.8% of the dose. After topical application of [14C]MSK (250 mg/kg; 50 μCi/kg), approximately 40% of the dose was absorbed and 84.5% of the absorbed dose was excreted into the urine (36% of the total dose). Urinary metabolites were similar to those described for oral administration. Importantly, [14C]-equivalents were not detected in the blood at any time after dermal administration. These results indicate that the rate of MSK clearance is equivalent to its rate of absorption, and tissue exposure to intact MSK is expected to be limited.
• Sauer, J., Bao, J., Smith, R. L., Mcclure, T. D., Mayersohn, M., Pillai, U., Cunningham, M. L., & Sipes, I. G. (1997). Absorption, disposition kinetics, and metabolic pathways of cyclohexene oxide in the male Fischer 344 rat and female B6C3F₁ mouse. Drug Metabolism and Disposition, 25(3), 371-378.
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  PMID: 9172957;Abstract: Cyclohexene oxide (CHO) is a monomer intermediate used in the synthesis of pesticides, pharmaceuticals, and perfumes. Although CHO has a variety of industrial uses where direct human exposure is possible, very little is known about its fate in the body. Therefore, the objectives of this study were to determine the absorption, distribution, metabolism, and excretion of cyclohexene oxide after oral, intravenous, and dermal exposure in male Fischer 344 rats and female B6C3F1 mice. After intravenous administration of [14C]CHO (50 mg/kg), CHO was rapidly distributed, metabolized, and excreted into the urine. Plasma concentrations of CHO rapidly declined and were below the limit of detection within 60 min. Average (±SD) values for terminal disposition half-life, apparent volume of distribution at steady-state, and systemic body clearance were: 19.3 ± 1.6 min; 0.44 ± 0.08 liter/kg; and 31.3 ± 0.5 ml/kg * min, respectively. After oral administration of [14C]CHO (10 and 100 mg/kg), it was found that 14C-equivalents were rapidly excreted in the urine of both species. At 48 hr, the majority of the dose (73-93%) was recovered in urine, whereas fecal elimination accounted for only 2-5% of the dose. At no time after oral administration was parent CHO detected in the blood. However, its primary metabolite cyclohexane-1,2-diol was present for different lengths of time depending on the dose. Four metabolites were detected and identified in mouse urine by MS: cyclohexane- 1,2-diol; cyclohexane-1,2-diol-O-glucuronide; N-acetyl-S-(2- hydroxycyclohexyl)-L-cysteine; and cyclohexane-1,2-diol-O-sulfate. The sulfate conjugate was not present in rat urine. Topical application of [14C]CHO (60 mg/kg) provided poor absorption in both species. The majority of 14C-equivalents applied dermally were recovered from the charcoal skin trap (~90% of the dose). Only 4% of the dose was absorbed, and the major route of elimination was via the urine. To evaluate the toxicity of CHO, animals were given daily doses of CHO orally and topically for 28 days. No statistically significant changes in final body weights or relative organ weights were noted in rats or mice treated orally with CHO up to 100 mg/kg or up to 60 mg/kg when given topically. Very few lesions were found at necropsy, and none were considered compound related. In conclusion, regardless of route, CHO is rapidly eliminated and excreted into the urine. Furthermore, after either oral or dermal administration, it is unlikely that CHO reaches the systemic circulation intact due to its rapid metabolism, and is therefore unable to cause toxicity in the whole animal under the test conditions used in this study.
• Sauer, J., Smith, R. L., Bao, J., Kattnig, M. J., Kuester, R. K., Mcclure, T. D., Mayersohn, M., & Sipes, I. G. (1997). Oral and topical absorption, disposition kinetics, and the metabolic fate of trans-Methyl styryl ketone in the male Fischer 344 rat. Drug Metabolism and Disposition, 25(6), 732-739.
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  PMID: 9193875;Abstract: trans-Methyl styryl ketone (MSK; trans-4-phenyl-3-buten-2-one) is a β- unsaturated ketone that has a wide range of uses in industry and is present in numerous consumer products. Although MSK has been shown to be positive in several in vitro mutagenic assays, it does not seem to be overtly toxic in animal models. This lack of toxicity may relate to its poor absorption and/or rapid elimination. However, little is known about the fate of MSK in the body. Studies were conducted to characterize the absorption, and disposition kinetics of MSK after intravenous, oral, and topical administration to male Fischer 344 rats. After intravenous administration of [14C]MSK (20 mg/kg, 120 μCi/kg), blood concentration-time data could be characterized with a biexponential equation and apparent first-order elimination kinetics. The following pharmacokinetic parameter values were obtained (mean ± SD): terminal disposition half-life, 17.7 ± 0.08 min; apparent steady-state volume of distribution, 0.89 ± 0.14 liters/kg; systemic body clearance, 68.9 ± 10.0 ml/kg * min; and mean residence time, 13.1 ± 2.2 min. Within 48 hr, 95.5% of the dose was excreted in the urine and 2.7% in the feces. The major blood metabolite after intravenous administration was identified by GC/MS as the 4-phenyl-3-buten-2-ol (methyl styryl carbinol). After oral administration of [14C]MSK (200 mg/kg, 100 μCi/kg), 96.6% of the dosed radioactivity was recovered in the urine and 4.8% in the feces within 48 hr. Major urinary metabolites identified by LC-MS/MS and quantified by HPLC radioassay were N- phenylacetyl-L-glycine (64.9% of dose) and N-benzyl-L-glycine (9.9% of dose). Parent compound could not be detected in the blood after oral administration, and 14C-equivalents in the blood never exceeded 1.3% of the dose. Results suggest near-total presystemic elimination of the oral dose. After topical application of [14C]MSK (250 mg/kg, 50μCi/kg), >60% of the dose was absorbed, and the majority of the dose was excreted into the urine (55% of dose) in the form of metabolites. Urinary metabolites were similar to those described after oral administration. 14C-equivalents were not detected in the blood at any time after topical administration. These results indicate that MSK is almost totally metabolized before systemic distribution after oral or topical administration. The systemic exposure dose of MSK seems to be exceedingly low at the doses studied herein.
• Tannenbaum, S., Boxenbaum, H., & Mayersohn, M. (1997). Allometric analysis of organ extraction ratios.. Journal of pharmaceutical sciences, 86(11), 1319-1320.
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  PMID: 9383748;
• Fruncillo, R., Troy, S., Parker, V., Mayersohn, M., Hicks, D., Kraml, M., Battle, M., & Chiang, S. (1996). Pharmacokinetics of the aldose reductase inhibitor tolrestat: Studies in healthy young and elderly male and female subjects and in subjects with diabetes. Clinical Pharmacology and Therapeutics, 59(6), 603-612.
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  PMID: 8681485;Abstract: Tolrestat is an aldose reductase inhibitor undergoing clinical trials in diabetic subjects that may reduce the severity of chronic tissue damage associated with hyperglycemia. These studies were conducted to evaluate the pharmacokinetics of tolrestat in healthy young and elderly male and female subjects and in young and elderly subjects with diabetes. The drug was administered in a multiple-dose regimen, and steady-state parameters were obtained. There were no important gender-related differences, but mean values for apparent oral clearance, renal clearance, and corresponding unbound parameters were significantly lower for the elderly healthy subjects than for the young healthy subjects. The drug is highly bound to plasma proteins, and the unbound fraction (0.75%) did not differ among the subjects. The results from young and elderly diabetic subjects suggest. that diabetes per se has no influence on tolrestat disposition but that there is an age-related reduction in apparent oral clearance (30 versus 18 ml/hr/kg) and a corresponding increase in the minimum steady-state plasma concentration (1.2 versus 1.9 μg/ml). These data indicate a possible need to reduce the dose of tolrestat in elderly subjects, assuming the same concentration-response relationship.
• Hutchaleelaha, A., & Mayersohn, M. (1996). Influence of activated charcoal on the disposition kinetics of methamphetamine enantiomers in the rat following intravenous dosing. Journal of Pharmaceutical Sciences, 85(5), 541-545.
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  PMID: 8742948;Abstract: Methamphetamine (MAP) is a central nervous system stimulant that is widely abused by populations of several countries. There is no specific antidote for the treatment of an overdose. Activated charcoal administered orally has been used to enhance the systemic elimination of certain toxic substances via 'gastrointestinal dialysis'. The results of in vitro studies have shown that MAP can be rapidly adsorbed from solution by activated charcoal. We have evaluated the effect of a single oral dose of activated charcoal on the disposition kinetics of MAP following a short iv infusion. Male Sprague- Dawley rats were given an oral dose of activated charcoal (Actidose-aqua, 1 g/kg) 10 min before a short iv infusion of racemic MAP; whereas the control group was given an equivalent volume of water. Enantiomers of MAP and metabolites in serum and urine were analyzed by an enantiomer-specific method which employed HPLC and detection of a fluorescent derivative. There were no differences in any of the disposition parameters between the two groups. Within each group, the clearance (CL(S)) of l-MAP was greater than that of d- MAP. However, there were no differences in the steady-state volume of distribution (V(SS)). The CL(S) (mL/(min kg)) and V(SS) (L/kg) values for l- and d-MAP in the control group were (mean ± SD): 85.8 ± 20.4, 48.7 ± 17.9, 2.64 ± 1.16, and 2.90 ± 1.36, respectively. The corresponding values in the charcoal-pretreated group were (mean ± SD): 57.4 ± 23.4, 51.1 ± 20.7, 2.79 ± 1.32, and 2.98 ± 1.47. These results suggest that oral activated charcoal does not enhance the elimination of MAP from the body.
• Pillai, U. A., Ziegler, T. L., Wang, D. X., Kattnig, M. J., McClure, T., Liebler, D. C., Mayersohn, M., & Sipes, I. G. (1996). 3,3',4,4'-Tetrachloroazobenzene absorption, disposition, and metabolism in male Fischer 344 rats. Drug Metabolism and Disposition, 24(2), 238-244.
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  PMID: 8742237;Abstract: 3,3',4,4'-Tetrachloroazobenzene (TCAB) is a contaminant generated during the synthesis of 3,4-dichloroaniline and 3,4-dichloroaniline-derived pesticides. TCAB is isosteric to 2,3,7,8-tetrachlorodibenzo-p-dioxin and has been shown to bind to the Ah receptor. Following oral administration of [14C]TCAB (3.2 and 32 mg/kg), 39-45% of the dosed radioactivity was excreted into the urine and 53-56% was recovered in the faces within 48 hr. Less than 6% of the dosed radioactivity remained in the tissues examined at 96 hr. After intravenous administration (3.2 mg/kg), 33% of the dose was excreted in the bile during 6 hr. TCAB metabolites in urine were identified using LC/MS. The major metabolites were sulfate ester conjugates of hydroxylated mono- or dichloroaniline derivatives. Some of these metabolites were also acetylated. After intravenous administration, the disappearance of [14C]TCAB from blood was monitored, and the pharmacokinetic profile was consistent with a two-compartment model. Pharmacokinetic parameters reveal that the compound is readily cleared from the blood with a t( 1/2 ) of 4.0 hr, clearance of 12.3 ml/min · kg, and an apparent volume of distribution of 4.3 liters/kg. The absolute oral bioavailability was determined to be 30%. The extensive azo reduction of TCAB decreases its systemic absorption after oral administration and thereby limits the amount of parent compound available to interact with the Ah receptor and decreases the Ah receptor-mediated toxicity.
• Sukbuntherng, J., Martin, D. K., Pak, Y., & Mayersohn, M. (1996). Characterization of the properties of cocaine in blood: Blood clearance, blood to plasma ratio, and plasma protein binding. Journal of Pharmaceutical Sciences, 85(6), 567-571.
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  PMID: 8773950;Abstract: As part of a study to examine cocaine disposition and interaction with ethanol, it was necessary to characterize various properties of cocaine in the blood of the experimental animal. All studies were conducted using blood from healthy adult male Sprague-Dawley rats. Cocaine was incubated in whole blood at 37 °C at concentrations of 500-4000 ng/mL. The apparent first-order rate constant for cocaine loss was independent of concentration. Blood clearance, calculated assuming blood volume to be 64 mL/kg, was estimated to be 0.056 ± 0.003 mL/(min·kg); a value considerably smaller than estimates of systemic clearance. The addition of NaF increased the rate of loss to form benzoylecgonine, as a result of increased chemical degradation and as a consequence of increased pH (to pH 8.0 over 30 h). This NaF-enhanced degradation was abolished when NaF was added to blood buffered to pH 7.4. Ethanol had no influence on cocaine degradation, and there was no evidence of cocaethylene (ethylcocaine) formation. Blood to plasma ratios determined in spiked and authentic samples were constant (0.94-1.05 and 0.99-1.03, respectively) and independent of concentration (100-1500 ng/mL) and pH (7.2-7.6). This ratio was not influenced by NaF or ethanol. The unbound fraction (f(u)) of cocaine determined in spiked plasma varied from 0.62 to 0.63 over the concentration range (75-2025 ng/mL). Ethanol had no effect on binding. The values for f(u) determined from authentic blood samples taken from rats dosed intravenously with cocaine (10 mg/kg) ranged from 0.67 to 0.69 (over the concentration range 300- 1500 ng/mL). Cocaine plasma protein binding was independent of concentration but depended upon plasma pH (f(u), 0.765 and 0.486, at pHs 7.0 and 7.8, respectively).
• Tannenbaum, S. J., Sinha, V., & Mayersohn, M. (1996). Potential errors in the use of body burden calculations for estimation of toxicokinetic parameters. Fundamental and Applied Toxicology, 30(1), 252-.
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  Abstract: The analysis of "body burden" data in toxicology research is extensive as evidenced by reports in the literature. Body burden is the amount of a xenobiotic that is present in the body at a given time. When body burden data are plotted on a semilogarithmic scale as a function of time, important toxicokinetic parameters such as elimination rate constant and disposition half-life may be estimated. This method of analysis is identical in concept to one frequently used in pharmacokinetics, namely the amount remaining to be excreted (ARE) method. Assuming a one-compartment model and first order kinetics, the ARE at time t is calculated using the equation: Xu∞-Xu, where Xu is the cumulative amount of drug excreted up to time t, and Xu∞ is the total amount of drug that is excreted through the renal pathway. Xu∞ is equal to: F'Xo, where X* is the dose, F' is the product of the bioavailability (F) and the fraction of drug excreted into urine (furine). The semilogarithmic plot of the ARE data versus time is used to estimate values of the elimination rate constant, elimination half-life, and F'. Using simulated data, we demonstrated the errors that result from the incorrect calculation of the ARE. These errors occur when X* is used instead of Xu∞, or urine is not collected to completion. We developed three methods whereby incorrect ARE data can be analyzed to find accurate estimates of the parameters. Of the three methods we recommend the use of Method 3 (the explicit fitting method). All simulations and optimizations were performed using SIMUSOLV.
• Valentine, J. L., Mayersohn, M., Wessinger, W. D., Arnold, L. W., & Owens, S. M. (1996). Antiphencyclidine monoclonal Fab fragments reverse phencyclidine- induced behavioral effects and ataxia in rats. Journal of Pharmacology and Experimental Therapeutics, 278(2), 709-716.
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  PMID: 8768722;Abstract: Antiphencyclidine monoclonal antibody binding fragments (anti-PCP Fab) were studied in rats as a possible treatment for phencyclidine (PCP) overdose. Each male Sprague-Dawley rat (n = 4 per group) received an i.v. dose of 1 mg/kg of PCP followed 5 min later (as toxicity maximized) by one of three treatments in a random cross-over design. The treatments were 1 ml of saline, a nonspecific polyclonal human Fab, or a high affinity (K(d) = 1.8 nM) anti-PCP monoclonal Fab. The doses of the nonspecific and anti-PCP Fab were 0.3, 1.0 and 3.0 times the mole equivalent (mol-eq) dose of PCP. Changes in locomotor activity and ataxia were the best indicators of PCP-induced behaviors among several time-dependent behavioral changes that were evaluated. PCP administration followed by saline treatment resulted in increases in locomotor activity and ataxia that declined to base line after 35 to 40 min. Anti-PCP Fab at 1.0 and 3.0 times the mol-eq dose of PCP significantly (P < .05) and rapidly reversed PCP-induced behaviors to base- line values. Although the 0.3 mol-eq dose of Fab appeared to slightly decrease the behavioral toxicity, the effects were not statistically different from controls in most cases. No significant effects on PCP-induced behaviors were observed after any dose of the nonspecific Fab. In addition, pharmacological and immunological specificity were tested further by treatment of MK-801 {(+)-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten- 5,10-imine-}-induced behavioral effects. MK-801 is a PCP-like, noncompetitive N-methyl-D-aspartate receptor antagonist which is structurally unrelated to PCP. The anti-PCP Fab treatment had no effect on MK-801-induced locomotor activity. These data clearly show that anti-PCP Fab is a specific PCP antagonist that can rapidly reverse PCP-induced behavioral toxicity in the rat.
• Ziegler, T. L., Pillai, U. A., Smith, R. L., Kattnig, M. J., Liebler, D. C., Mayersohn, M., & Sipes, I. G. (1996). Absorption and disposition kinetics of 3,3',4,4'- tetrachloroazoxybenzene in the male Fischer 344 rat. Drug Metabolism and Disposition, 24(9), 1009-1014.
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  PMID: 8886612;Abstract: 3,3',4,4'-Tetrachloroazoxybenzene (TCAOB) is a structural analog of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). It is formed as a byproduct during the synthesis of industrial products such as herbicides. TCAOB is a ligand for the Ah receptor and, at much higher doses, exhibits toxicities similar to TCDD. Although the reduced in vivo toxicity of TCAOB probably reflects differences in disposition, this study characterized its absorption and disposition kinetics. Male Fischer 344 rats were administered [ 14C]TCAOB (3.4 or 34 mg/kg po, 3.4 mg/kg iv), and the excretion of the radiolabel was monitored over 96 hr. After the low and high dose, 35% and 30% of the [ 14C]TCAOB were eliminated in the urine, with 55% and 54% eliminated in the faces. At 96 hr, the adipose tissue:blood ratios of [ 14C]TCAOB equivalents were 8 and 26 for the low and high doses, respectively. After the intravenous dose of TCAOB, the adipose tissue:blood ratio was 21 at 96 hr. Other tissue:blood ratios were of little significance (0.06-3.2). Pharmacokinetic parameters indicate that the parent molecule is cleared from blood with an average half-life of 7 hr and an average clearance of 11 ml/min · kg. Absolute bioavailability was calculated to be ~9%. Urine contained a variety of dichlorolaniline conjugates, which support the importance of azo reduction in the disposition of TCAOB. When compared with TCDD, the absorption of TCAOB is greatly reduced and the elimination of metabolites greatly enhanced. Therefore, at equal molar oral doses, TCAOB would express lower levels of Ah receptor-mediated toxicity than those defined for TCDD.
• Chow, H. -., Wu, Y., & Mayersohn, M. (1995). Pharmacokinetics of amphotericin B in rats as a function of dose following constant-rate intravenous infusion. Biopharmaceutics and Drug Disposition, 16(6), 461-473.
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  PMID: 7579028;Abstract: Amphotericin B (AmB) is widely used for the treatment of systemic mycoses. The current therapeutic regimens for this drug are complex and somewhat empirical, in part because of very limited information about the disposition kinetics of this agent. In this study, we examined the disposition kinetics of AmB as a function of dose and estimated clearance values using a steady state study design in an animal model. Groups of male Sprague-Dawley rats were given different two-step infusion regimens to achieve three different steady state concentrations (i.e., three different total infused doses). We observed no significant differences in systemic clearance among the three AmB doses studied. Similarly, only small differences were seen in volumes of distribution as a function of dose. However, renal clearance decreased significantly as the total infused dose was increased (0.76 ± 0.33, 0.86 ± 0.24, and 0.37 ± 0.04 mL min-1 kg-1 for the low-medium and high-dose groups, respectively; p < 0.05). Signs of renal impairment were observed in the high-dose group, as documented by decreased creatinine clearance. Dose-dependent renal clearance may have been due either to nephrotoxicity associated with the high-dose of AmB and/or to saturation of an active secretion process. Furthermore, clearance values estimated from steady state conditions were similar to those from time-averaged values (based on the estimation of area under the plasma concentration-time profile). This suggests that clearance calculations from time-averaged concentrations provide reasonable estimates, since steady state plasma concentrations could be reliably determined. However, the possibility that a true tissue steady state condition was not achieved with our study design cannot be ruled out. Further investigation is necessary to identify the renal excretion mechanisms of AmB and to reach steady state tissue concentration to confirm the estimation of systemic clearance.
• Mayersohn, M., & Guentert, T. W. (1995). Clinical pharmacokinetics of the monoamine oxidase-A inhibitor moclobemide. Clinical Pharmacokinetics, 29(5), 292-332.
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  PMID: 8582117;Abstract: There has been a resurgence of interest in the use of monoamine oxidase (MAO) enzyme inhibitors for the treatment of depression. Unlike the first-generation MAO inhibitors, the current drugs are readily reversible in their action, resulting in far less concern about interactions with certain foods and drugs which could lead to serious presser effects. Furthermore, the current drugs are Ear more selective in their actions as a result of the ability to affect either the MAO-A or the MAO-B isoenzyme. Moclobemide is an example of a reversible MAO-A inhibitor which has been extensively studied and whose pharmacokinetic, clinical pharmacological and toxicological profiles have been thoroughly defined. Moclobemide has a short disposition half-life and intermediate values for systemic clearance and volume of distribution; half-life increases somewhat with dose. The drug is completely metabolised by the liver. Moclobemide is rapidly and completely absorbed following oral administration in a variety of dosages and forms. The drug has a high intrinsic (apparent oral) clearance which results in a substantial hepatic first-pass effect and, while there is marked interindividual variation, differences within an individual are small. A time- and dose-dependence is observed with multiple oral administration: clearance decreases with administration during the first week and thereafter remains constant. The exact mechanism of this effect is not known, but it may reflect inhibition of elimination by metabolites (the kinetics may always be described as being first-order). Moclobemide disposition is not affected by renal disease, nor is there substantial alteration with advanced age. Liver disease causes a dramatic reduction in clearance; dosage must be adjusted for patients with liver disease. There is minimal transfer of the drug into breast milk, such that breast-feeding neonates are exposed to only a very small dose of the drug. Moclobemide administration results in a minimal interaction with exogenous amines (e.g. tyramine and presser amine drugs); the so-called 'cheese effect' is therefore of little concern. As a result, the drug has an excellent tolerability profile both within the therapeutic dose range and in overdose (no deaths have been attributed to moclobemide intoxication per se). Cimetidine inhibits the elimination of moclobemide. Moclobemide appears to affect several isoenzymes of the cytochrome P450 (CYP) system (CYP2C19, CYP2D6 and CYP1A2). The adverse events profile of moclobemide indicates only mild and transient effects at a relatively low rate of occurrence.
• Sukbuntherng, J., Hutchaleelaha, A., Chow, H. -., & Mayersohn, M. (1995). Separation and quantitation of the enantiomers of methamphetamine and its metabolites in urine by HPLC: Precolumn derivatization and fluorescence detection. Journal of Analytical Toxicology, 19(3), 139-147.
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  PMID: 7564290;Abstract: To study the disposition kinetics of methamphetamine (MAP), we have developed a sensitive high-performance liquid chromatographic (HPLC) assay to quantitate the enantiomers of MAP and its major metabolites, amphetamine (AP), p-hydroxy-methamphetamine (p-OH-MAP), and p-hydroxyamphetamine (p-OH- AP), the latter two of which are hydroxylated metabolites, in rat urine. To determine conjugated hydroxylated metabolites, urine samples were treated with β-glucuronidase. Both hydrolyzed and nonhydrolyzed p-OH-MAP and p-OH- AP were extracted into ethyl acetate and back extracted with 0.05M HCl. To determine MAP and AP, urine samples were extracted with benzene, followed by back extraction into 0.05M HCl. The acid layer was collected, and to it was added (-)-1-(9-fluorenyl)ethyl chloroformate (FLEC) for the derivatization of MAP and its metabolites. Derivatization was allowed to proceed for 24 h at room temperature. The derivatized products were separated on a C18 column with a mobile phase consisting of acetate buffer (pH 3.6)-acetonitrile- tetrahydrofuran. Quantitation was achieved using a fluorescence detector at an excitation wavelength of 265 nm and an emission wavelength of 330 nm. Linear standard curves were obtained over the concentration range of 5-100 ng/mL. The interday and intraday coefficients of variation for the assay for all eight enantiomers at 10 and 75 ng/mL were less than 13%. The detection limit was 5 ng/mL or 0.5 ng on-column. The method was applied to quantitate the concentration of MAP and its metabolites in rat urine following a short intravenous infusion of 7.5 mg./kg d,l-MAP. There were no significant differences in total recovery of MAP enantiomers in urine (at p of .05), but there was a greater excretion of d-AP compared with I-AP (p < .005). The urinary recovery of the I-enantiomer was consistently higher than the d-form for both p-OH-MAP and p-OH-AP (p < .02 and p < .002, respectively). These data suggest a stereoselective disposition of MAP in rats.
• Sukbuntherng, J., Walters, A., Chow, H. -., & Mayersohn, M. (1995). Quantitative determination of cocaine, cocaethylene (ethylcocaine), and metabolites in plasma and urine by high-performance liquid chromatography. Journal of Pharmaceutical Sciences, 84(7), 799-804.
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  PMID: 7562427;Abstract: A sensitive HPLC assay was developed to quantitate the relatively nonpolar compounds cocaine, cocaethylene (ethylcocaine), norcocaine, and norcocaethylene, as well as the relatively polar metabolites benzoylecgonine and benzoylnorecgonine, in rat plasma and urine. The assay in plasma employed two successive liquid-liquid extractions and separate injections onto two different columns (C8 and C18) to separate and quantitate the relatively polar and nonpolar compounds. In urine, the procedure employed a liquid- liquid extraction followed by solid-phase extraction (C18 light-load cartridges) and two separate injections as for plasma. The UV absorbance of the effluent was monitored at 235 nm. Linear standard curves were obtained over the concentration ranges of 25 to 1000 ng/mL and 5 to 250 ng/mL in plasma and urine, respectively. The inter- and intraday coefficients of variation for the assay of all compounds in plasma and urine were
• Dart, R. C., Hurlbut, K. M., Maiorino, R. M., Mayersohn, M., Aposhian, H., & Hassen, L. V. (1994). Pharmacokinetics of meso-2,3- dimercaptosuccinic acid in patients with lead poisoning and in healthy adults. The Journal of Pediatrics, 125(2), 309-316.
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  PMID: 8040783;Abstract: We compared the pharmacokinetics of meso-2,3-dimercaptosuccinic acid (DMSA) in three children with lead poisoning, three adults with lead poisoning, and five healthy adult volunteers. All subjects received DMSA orally. Maximum blood concentration and time to maximum blood concentration of total DMSA concentration were not statistically different among the groups. Unaltered DMSA was detected in the blood of all poisoned patients but in only one of five healthy volunteers. Elimination half-life of total DMSA (parent drug plus oxidized metabolites) was longer in children with lead poisoning (3.0 ± 0.2 hours) than in adults with lead poisoning (1.9 ± 0.4 hours) and healthy adults (2.0 ± 0.2 hours). Renal clearance of total DMSA was greater in healthy adults (77.0 ± 13.2 ml/min per square meter) than in either adults (24.7 ± 3.3 ml/min per square meter) or children with lead poisoning (16.6 ml/min per square meter); renal clearance of the metabolites of DMSA was also greater in healthy adults (64.6 ± 10.1 ml/min per square meter) than in either adults (35.4 ± 8.4 ml/min per square meter) or children with lead poisoning (19.5 ml/min per square meter). The DMSA appeared to enter the erythrocytes of patients with lead poisoning to a greater extent than in healthy adults. We conclude that renal clearance of DMSA and its metabolites may be impaired and that the distribution of DMSA in children with lead poisoning may be different from that in adults. (J PEDIATR 1994;125:309-16). © 1994 Mosby, Inc. All rights reserved.
• Hurlbut, K. M., Maiorino, R. M., Mayersohn, M., Dart, R. C., Bruce, D. C., & Aposhian, H. V. (1994). Determination and metabolism of dithiol chelating agents XVI: Pharmacokinetics of 2,3-dimercapto-1-propanesulfonate after intravenous administration to human volunteers. Journal of Pharmacology and Experimental Therapeutics, 268(2), 662-668.
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  PMID: 8113976;Abstract: The pharmacokinetics of 2,3-dimercaptopropane-1-sulfonate (DMPS), an effective chelating agent for mercury, were determined in five healthy adults after i.v. administration of 3.0 mg/kg of DMPS. DMPS is rapidly transformed to disulfide forms; 15 min after administration, only 12% of the total DMPS detected in blood was present as the parent drug. DMPS and its metabolites were eliminated primarily by the kidneys. By 96 hr after administration, 12% of the total DMPS found in the urine was excreted as the parent drug (10% of the administered dose) and 88% was excreted as disulfide metabolites (74% of the administered dose). The disposition of parent drug was described by a biexponential equation with an elimination half-life of 1.8 hr. By contrast, the elimination half-life of total DMPS was 20 hr. The oral bioavailability of the parent drug was found in a separate study to be 39%. Mercury excretion in healthy volunteers correlated well with the urinary excretion of both the parent drug (n = .94) and the disulfide metabolites (r2 = .96).
• Hutchaleelaha, A., Sukbuntherng, J., Chow, H. -., & Mayersohn, M. (1994). Disposition kinetics of d- and I-amphetamine following intravenous administration of racemic amphetamine to rats. Drug Metabolism and Disposition, 22(3), 406-411.
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  PMID: 8070317;Abstract: Amphetamine (AP), a chiral drug, displays stereoselective differences in biological action. The effect of stereochemistry on the disposition kinetics of the enantiomers has not been thoroughly studied. We examined the disposition kinetics of AP in rats using a sensitive precolumn derivatization HPLC method that can separate the enantiomers of AP and its metabolites. Male Sprague-Dawley rats were given a short intravenous infusion of racemic AP (15 mg/kg). The systemic and renal clearances, steady-state volume of distribution, and terminal half-life for I-AP were (mean ± SD), respectively: 65.6 ± 9.25 ml/min · kg; 15.4 ± 2.55 ml/min · kg; 4.33 ± 0.71 liters/kg; and 0.96 ± 0.13 hr. The corresponding values for d-AP were: 50.8 ± 6.88 ml/min · kg; 12.5 ± 2.02 ml/min · kg; 3.84 ± 0.55 liters/kg; and 1.12 ± 0.09 hr. There are statistically significant differences between the enantiomers in all pharmacokinetic parameters except half-life. About 40% of the I-AP dose was excreted in urine as I-p-hydroxyamphetamine and 24% as intact drug. The corresponding values for d-AP were 32% and 26%, respectively. p-Hydroxyamphetamine was primarily excreted into urine as the conjugated form. These data indicate stereoselective differences in the pharmacokinetics of the enantiomers of AP after administration of racemic drug in the rat.
• Hutchaleelaha, A., Walters, A., Chow, H., & Mayersohn, M. (1994). Sensitive enantiomer-specific high-performance liquid chromatographic analysis of methamphetamine and amphetamine from serum using precolumn fluorescent derivatization. Journal of Chromatography B: Biomedical Sciences and Applications, 658(1), 103-112.
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  PMID: 7952109;Abstract: In order to study the stereoselective disposition of methamphetamine (MAP), a widely abused drug, we have developed a sensitive HPLC assay to separate and quantitate the enantiomers of MAP and amphetamine (AP) in rat serum. Serum samples to which was added aniline sulfate (internal standard) were alkalized with 0.02 M carbonate buffer (pH 10.6) and extracted with ethyl acetate. Following back extraction with hydrochloric acid, neutralization, and reconstitution, the sample was derivatized with (-)-fluorenylethyl chloroformate overnight at room temperature. The derivatized products were separated following injection onto a reversed-phase C18 column. The mobile phase consisted of 0.02 M acetate buffer-acetonitrile-tetrahydrofuran (46:39:15, v/v). The fluorescent intensity of the effluent was monitored at excitation and emission wavelengths of 265 and 330 nm, respectively. The derivatized aniline, R-, S-AP, R- and S-MAP had retention times of 21.0, 22.6, 23.6, 27.7 and 29.0 min, respectively. Linear standard curves were obtained over the concentration range of 5-250 ng/ml. The inter-day and intra-day coefficients of variation for the assay of all four compounds at 12.5, 50.0 and 250 ng/ml were in the range of 2.1-18.6%. The method was applied to quantitate the concentrations of MAP and AP enantiomers in rat serum following a short term intravenous infusion of racemic MAP (15 mg/kg). There were no differences in serum concentrations of MAP enantiomers but the concentrations of S-AP were consistently greater than those of R-AP. These data suggest a stereoselective disposition for the formation and/or elimination of amphetamine. © 1994.
• Mayersohn, M. (1994). Pharmacokinetics in the elderly. Environmental Health Perspectives, 102(SUPPL. 11), 119-124.
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  PMID: 7737036;PMCID: PMC1566768;Abstract: Animals undergo substantial changes in many physiologic and biochemical functions as a natural consequence of aging. In the absence of disease or other pathologic conditions, these changes occur in a gradual manner with time (generally expressed as a fractional or percentage change in that function per year or decade). Furthermore, for any given function and at any given chronologic age, there is large variation in that function among individuals. Given the increase in life expectancy, the substantial increase in the number of elderly (and aged elderly) in the population, and the escalating costs of health care, there is great interest in learning more about the risks associated with aging as a result of toxic exposure. Are the elderly at greater risk than younger adults to the toxic effects of drugs and environmental exposure? Is the elderly population an inherently more sensitive one?
• Pieniaszek Jr., H. J., Davidson, A. F., McEntegart, C. M., Quon, C. Y., Sampliner, R. E., & Mayersohn, M. (1994). The effect of hepatic disease on the disposition of moricizine in humans. Biopharmaceutics and Drug Disposition, 15(3), 243-252.
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  PMID: 7880984;Abstract: The pharmacokinetics of moricizine and two of its metabolites, moricizine sulfoxide and phenothiazine-2-carbamic acid ethyl ester sulfoxide, were studied in healthy control subjects and in patients with chronic liver disease (cirrhosis). Moricizine disposition was significantly altered by hepatic cirrhosis. Compared to healthy subjects, the hepatic disease patients had an increased C(max) (59%), an increased t( 1/2 ) (141%), and a reduced plasma clearance (71%). Additionally, small but statistically significant increases were observed for t(max) and the fraction of moricizine not bound to plasma proteins in patients with hepatic disease. The elimination of both moricizine metabolites was also altered by hepatic dysfunction as indicated by significantly prolonged terminal half-lives. Furthermore, there was a reduction in the conversion of moricizine to moricizine sulfoxide. Both hepatic blood flow and hepatic metabolizing capacity were assessed in all subjects and patients by administration of indocyanine green and antipyrine, respectively. Indocyanine green and antipyrine plasma clearances were decreased by 38 and 51%, respectively, indicating that both functions were diminished by hepatic cirrhosis. We conclude that the moricizine dose required for arrhythmia patients with hepatic disease should be lower, and perhaps, the dosing frequency should be less than in patients with normal liver function.
• Mayersohn, M., & Hamilton, R. (1993). Relationship between the terminal disposition half-life and mean residence time in multicompartment models. Drug Metabolism and Disposition, 21(6), 1172-1173.
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  PMID: 7905402;
• Zheng, W., Winter, S. M., Mayersohn, M., Bishop, J. B., & Sipes, I. G. (1993). Toxicokinetics of sulfasalazine (salicylazosulfapyridine) and its metabolites in B6C3F₁ mice. Drug Metabolism and Disposition, 21(6), 1091-1097.
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  PMID: 7905389;Abstract: The toxicokinetics of salicylazosulfapyridine (SASP) and its metabolites were investigated in male and female B6C3F1 mice either following single intravenous (5 mg/kg) or oral (67.5, 675, 1350, and 2700 mg/kg) doses, or following three consecutive daily oral doses (675, 1350, and 2700 mg/kg). Plasma concentrations of SASP and its metabolites were quantified by HPLC. Upon intravenous administration, SASP rapidly disappeared from blood with a mean residence time of 0.45-0.78 hr. The only metabolite of SASP found in plasma after an intravenous dose was sulfapyridine (SP). In both sexes, the absolute oral bioavailability of SASP ranged between 16.6-18.2% at a dose of 67.5 mg/kg, and between 2.6-8.7% at doses of 675-2700 mg/kg. Following oral administration of SASP, both SP and AcSP were identified in plasma. The area under the plasma concentration-time curves (AUC) of SP at all four oral doses were ~21- to 32-fold or 5- to 25-fold greater than those of SASP in male or female mice, respectively. The acetylated form of SP and AcSP, produced AUC values higher than SASP but much less than SP. Multiple oral doses with SASP did not alter the temporal patterns of SASP absorption and elimination in comparison to a single dose. However, SP accumulated in both sexes following multiple oral doses. A gender-dependent difference in toxicokinetic profiles for SASP and SP was also observed. Female mice displayed a higher C(max) of SASP and SP than did male mice. Although the volume of distribution of SASP was similar in both sexes, the systemic clearance of SASP in males was about twice that observed in females. The results indicated that after SASP administration, the metabolites SP and AcSP displayed higher and more prolonged plasma concentration-time profiles than parent SASP. Therefore, SP may accumulate in the body following repeated dosing and contribute to the genotoxicity observed following administration of high doses of SASP.
• Burgess, J. L., Dart, R. C., Egen, N. B., & Mayersohn, M. (1992). Effects of constriction bands on rattlesnake venom absorption: A pharmacokinetic study. Annals of Emergency Medicine, 21(9), 1086-1093.
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  PMID: 1514719;Abstract: Study objective: To determine whether the use of a constriction band alters systemic absorption of rattlesnake venom in pigs and whether constriction band use alters local swelling. Design: Using a crossover design, five pigs were studied with and without the use of a constriction band. 125l-Labeled Western Diamondback rattlesnake (Crotalus atrox) venom was injected subcutaneously into one foreleg. The protocol was repeated using the opposite foreleg six days later. The constriction band was applied at the time of injection and removed four hours later. Plasma radioactivity and leg circumference were measured serially. Results: Maximum plasma venom concentration and area under the venom concentration-time curve were compared in trials with and without constriction band. Within the initial four hours, application of a constriction band decreased maximum plasma venom concentration by 25% and area under the venom concentration-time curve by 33% (P < .05). After the constriction band removal at four hours, maximum plasma venom concentration and the area under the venom concentration-time curve were not significantly different between groups. Application of a constriction band did not result in a statistically significant increase in maximum leg circumference as compared with trials without a constriction band. Conclusion: The use of a constriction band was effective in reducing venom absorption while it was in place (reduced area under the venom concentration-time curve and maximum plasma venom concentration in the cuffed group), and constriction band removal did not result in a significant increase in maximum plasma venom concentration. Leg swelling was not affected by constriction band use. Because constriction band use delayed venom absorption without causing increased swelling, it may prove to be a useful first aid measure in human beings. © 1992 American College of Emergency Physicians.
• Chow, H. -., Cai, Y., & Mayersohn, M. (1992). Disposition kinetics of amphotericin B in rats: The influence of dose. Drug Metabolism and Disposition, 20(3), 432-435.
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  PMID: 1355720;Abstract: Amphotericin B (Am-B), an antifungal drug, has been used for the treatment of most disseminated fungal infections. The current therapeutic regimens for this drug are complex, at least in part as a result of limited pharmacokinetic information. In this study, we examined the disposition of Am-B as a function of dose in rats. Groups of male Sprague-Dawley rats were given Am-B by a 15-min iv infusion at three different doses. We observed no significant differences in systemic clearance among the Am-B doses studied (4.29 ± 1.42, 3.83 ± 0.29, and 3.92 ± 0.68 ml/min · kg for doses of 0.28, 0.45, and 0.84 mg/kg, respectively). Similarly, small differences were seen in volumes of distribution as a function of dose. We conclude that the disposition kinetics of Am-B were linear over the dose range studied.
• Chow, H. H., Hutchaleelaha, A., & Mayersohn, M. (1992). Inhibitory effect of 4-methylpyrazole on antipyrine clearance in rats. Life Sciences, 50(9), 661-666.
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  PMID: 1740974;Abstract: Pyrazole and 4-methylpyrazole (4-MP) are potent, effective inhibitors of alcohol dehydrogenase. Pyrazole and its derivatives also have been shown to affect the cytochrome P-450 dependent monooxygenase system. This study was performed to investigate the effect of 4-MP on the disposition kinetics of antipyrine (AP). Groups of male Fisher 344 rats were given an ip injection of 4-MP (100 mg/kg) or 4-MP HCl (equivalent to 4-MP 100 mg/kg) or an equivalent volume of saline. AP (20 mg/kg) was injected intravenously via the jugular vein catheter 30 minutes later. Blood samples were collected upto 24 hours and assayed by HPLC. 4-MP pretreatment significantly decreased AP clearance from 0.490 ± 0.032 to 0.095 ± 0.014 (4-MP HCl) and 0.076 ± 0.008 (4-MP) L/hr kg (p
• Mayersohn, M. (1992). Vitamin C bioavailability.. Journal of Nutritional Science and Vitaminology, Spec No, 446-449.
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  PMID: 1297786;Abstract: The above brief review indicates that the bioavailability of vitamin C in humans is complex and that our current understanding of that process and factors that influence it are incomplete. It is important that an overall pharmacokinetic scheme be developed and tested to completely describe the complex dispositional and absorption processes of the vitamin. Such information will provide a better understanding of the absorption and disposition of the vitamin per se. Furthermore, that information will permit us to better understand how those factors influence the participation of the vitamin in events associated with maintenance of health.
• Pieniaszek Jr., H. J., McEntegart, C. M., Mayersohn, M., & Michael, U. F. (1992). Moricizine pharmacokinetics in renal insufficiency: Reevaluation of elimination half-life. Journal of Clinical Pharmacology, 32(5), 412-414.
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  PMID: 1587958;
• Pieniaszek, H. J., McEntegart, C. M., Mayersohn, M., & Michael, U. F. (1992). Erratum: Moricizine pharmacokinetics in renal insufficiency: Reevaluation of elimination half-life (J Clin Pharmacol (1992) 32 (412-414)). Journal of Clinical Pharmacology, 32(7), 678-.
• Abdallah, H. Y., & Mayersohn, M. (1991). The preparation and evaluation of a tablet dosage form of cyclosporine in dogs. Pharmaceutical Research, 8(4), 518-522.
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  PMID: 1871050;Abstract: Cyclosporine (CsA) is commercially available for oral administration as a solution in olive oil with alcohol and an emulsifier. To improve its variable absorption and low patient acceptability, several oral formulations were prepared and tested in vitro and in vivo in dogs. A tablet formulation prepared by direct compression was then selected for comparison with the commercial oil solution placed into soft gelatin capsules. The study involved a randomized crossover design in six dogs. In order to determine absolute bioavailability and to compensate for any time-dependent changes in clearance, an intravenous tracer dose of 3H-CsA was administered along with each oral test product on each of two occasions. Absolute bioavailability (mean ± SD) was 46.0 ± 11.1 and 45.4 ± 9.9% for the capsules and tablets, respectively. C(max), t(max), and mean absorption time were not significantly different between the two products. No differences were observed in the pharmacokinetics of the intravenously administered CsA in the two experiments, which were separated by 8-13 days. We conclude that the proposed tablet formulation for CsA is equivalent in dogs to the commercial dosage form placed into soft gelatin capsules.
• Abdallah, H. Y., Mayersohn, M., & Conrad, K. A. (1991). The influence of age on salicylate pharmacokinetics in humans. Journal of Clinical Pharmacology, 31(4), 380-387.
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  PMID: 2037713;Abstract: The pharmacokinetics of salicylate after a single oral solution dose of 600 mg of sodium salicylate were investigated in 22 male subjects. Subjects were healthy nonsmokers and were not taking any regular medication. The plasma concentration and urinary excretion of salicylic acid and its metabolite, salicyluric acid, as well as the urinary excretion of salicyl glucuronides were determined. Urinary recovery essentially accounted for the administered dose and was not influenced by age, nor was the apparent oral clearance of salicylic acid. Assuming no presystemic elimination, it could be concluded that systemic availability is unaffected by age. An increase in the apparent volume of distribution, V(area), and a decrease in the maximum plasma salicylic acid concentration with age were observed. Renal clearance of salicyluric acid decreased significantly with age and was found to correlate significantly with creatinine clearance. The authors conclude that age does not have a major influence on salicylate disposition in healthy adult men.
• Khor, S. P., & Mayersohn, M. (1991). Potential error in the measurement of tissue to blood distribution coefficients in physiological pharmacokinetic modeling: Residual tissue blood. I. Theoretical considerations. Drug Metabolism and Disposition, 19(2), 478-485.
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  PMID: 1676658;Abstract: Physiological pharmacokinetic models require the determination of tissue to blood distribution coefficients. A theoretical model has been developed and the resulting equations indicate that under certain conditions it is necessary to correct for the presence of drug in the residual blood remaining in the tissue. The potential error in ignoring this residual blood is expressed mathematically in terms of several important factors that include the anatomical features of the tissue (volume fractions of the blood, interstitial fluid, and cellular space) as well as the physicochemical properties of the drug (extent of binding in the blood and tissues). These theoretical considerations and resulting simulations have been applied to experimental literature data for several compounds (methotrexate, digoxin, and biperiden). We conclude that correction for the residual blood is necessary when the values of tissue to blood distribution coefficients are very small or large (relative to one) and when the volume fraction of the blood in tissue is substantial.
• Khor, S. P., Bozigian, H., & Mayersohn, M. (1991). Potential error in the measurement of tissue to blood distribution coefficients in physiological pharmacokinetic modeling: Residual tissue blood. II. Distribution of phencyclidine in the rat. Drug Metabolism and Disposition, 19(2), 486-490.
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  PMID: 1676659;Abstract: A model for predicting the magnitude of error (% Err) in measuring tissue concentrations of a compound that have not been corrected for residual blood in the tissue was previously developed. The model was tested using data for phencyclidine tissue distribution in the rat. It is shown that % Err may be expressed as a function of volume fraction of blood in tissue (V(F))(B) and tissue-to-blood distribution coefficient. Correction for residual blood is important when the volume fraction of the blood in the tissue is large and when the compound is not taken up substantially by the tissue. On the other hand, a correction may not be necessary when (V(F))(B) is small and uptake of the compound into the tissue is substantial.
• Khor, S. P., Johnson, S. L., & Mayersohn, M. (1991). Area-based estimation of the initial volume of distribution and elimination rate constant following intravenous bolus injection. Journal of Pharmaceutical Sciences, 80(11), 1042-1050.
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  PMID: 1815055;Abstract: We evaluate here an area term, the area under the rate of change of concentration-time curve (AURC), which allows the determination of the initial or central volume of distribution (V1). It has previously been shown that AURC is equal to the sum of the coefficients of a multiexponential equation and, therefore, V1 = dose/AURC. It is also shown that the normalized moment, AURC/AUC, is equal to the elimination rate constant, k10, where AUC is the area under the concentration-time curve. This area-based method to estimate V1 and k10 has been evaluated with simulation of three model equations and compared with nonlinear regression analysis of the same data. Random errors of 10 and 15% were introduced into the concentration values. The AURC method provides values of both parameters that are similar to those obtained from nonlinear regression analysis and which are reasonably accurate estimates of the theoretically correct values. The potential limitations of this area method are discussed. Good correlations were also observed for values of V1 and k10 obtained by AURC and regression methods for data obtained from the literature for 13 different drugs.
• Schoerlin, M., Mayersohn, M., Hoevels, B., Eggers, H., Dellenbach, M., & Pfefen, J. (1991). Cimetidine alters the disposition kinetics of the monoamine oxidase-A inhibitor moclobemide. Clinical Pharmacology and Therapeutics, 49(1), 32-38.
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  PMID: 1988238;Abstract: The influence of cimetidine on the absorption and disposition of moclobemide was examined in eight healthy male subjects. A single 100 mg intravenous and 100 mg oral dose of moclobemide was administered before and after 2 weeks of cimetidine administration (200 mg five times a day). The data on intravenous administration indicated that cimetidine produced a statistically significant alteration in the following disposition parameters (mean values for control versus cimetidine): systemic clearance, 46.6 versus 28.3 L/hr; mean residence time, 2.1 versus 3.2 hours; elimination half-life, 1.6 versus 2.3 hours. There was no significant difference in the steady-state volume of distribution. The absolute oral bioavailability of moclobemide increased significantly after cimetidine administration (54% versus 68%), as did the maximum plasma concentration after a single oral dose (575 versus 787 ng/ml). There were no differences in the mean absorption time or time to achieve maximum concentration. The values of systemic and apparent oral clearances of moclobemide after cimetidine administration were directly related to the corresponding control values before cimetidine. In contrast, the percentage change in clearance was essentially independent of the corresponding initial control clearance value.
• Schoerlin, M. -., Horber, F. F., Frey, F. J., & Mayersohn, M. (1990). Disposition kinetics of moclobemide, a new Mao-A inhibitor, in subjects with impaired renal function. Journal of Clinical Pharmacology, 30(3), 272-284.
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  PMID: 2312783;Abstract: A single intravenous and oral dose of moclobemide (Ro 11-1163) was administered to 13 subjects with varying degrees of renal impairment (creatinine clearances ranging from 0 to 40 mL/min). The resulting disposition and absorption parameters of moclobemide were more variable than but, with the exception of mean absorption time, were not significantly different from values obtained in another study conducted in 12 normal healthy subjects. There were no relationships between any of the disposition parameters and renal function as measured by creatinine clearance. The disposition of two metabolites of moclobemide were partially characterized from plasma data. One of these (Ro 12-8095) appears to be formation rate-limited and, from available data, behaves in a manner similar to what has been observed in normals. The other metabolite (Ro 12-5637) has a long apparent disposition half-life and is present in greater concentrations in the renally impaired compared to the normal subjects. The latter observation may reflect reduced elimination clearance in the renally impaired subjects. Based upon the results of this study there does not appear to be any need to alter the normal dosing regimen of moclobemide in subjects with renal impairment in order to achieve drug concentrations similar to those in healthy subjects.
• Stoeckel, K., Pfefen, J. P., Mayersohn, M., Schoerlin, M. P., Andressen, C., Ohnhaus, E. E., Frey, F., & Guentert, T. W. (1990). Absorption and disposition of moclobemide in patients with advanced age or reduced liver or kidney function. Acta Psychiatrica Scandinavica, Supplement, 82(360), 94-97.
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  PMID: 2248088;Abstract: Three different studies were conducted to assess the pharmacokinetics of moclobemide in subjects with conditions complicating dose determination. The first examined the absorption and disposition of moclobemide in an elderly population and compared these with results obtained in a group of normal young subjects. No significant differences were found between the groups in the intravenous (i.v.) parameters of disposition, and no differences with regard to disposition of the metabolic, Ro 12-8095. In addition, the minimum steady-state concentrations of moclobemide and the main plasma metabolite did not differ between the elderly and younger patients. In the second study, clearance tests in patients with cirrhosis of the liver confirmed that hepatic function is drastically reduced in this group of patients; it is therefore possible that moclobemide absorption and distribution might be influenced. In only 3 of the 12 patients investigated, slowly declining plasma concentrations after administration pointed to a severely limited elimination capacity for moclobemide. In the remaining 9 subjects, average values of several parameters changed significantly (t( 1/2 β), MRT and Cl), whereas V(ss) and renal clearance were not significantly altered. In patients with kidney dysfunction, there were no differences in kinetics between patients undergoing hemodialysis and those who were not. Compared with normal healthy volunteers, no differences were found for renal patients, with the exception of the mean absorption time, which was significantly prolonged. From these studies it can be concluded that, pharmacokinetically, neither age nor renal impairment require adjusting the dosage of moclobemide. Patients with liver cirrhosis, however, need to have the usual dose reduced to one half or one third, or else the dosage intervals can be increased to prevent cumulation.
• Egen, N. B., Bliss, M., Mayersohn, M., Owens, S. M., Arnold, L., & Bier, M. (1988). Isolation of monoclonal antibodies to phencyclidine from ascites fluid by preparative isoelectric focusing in the Rotofor. Analytical Biochemistry, 172(2), 488-494.
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  PMID: 3189790;Abstract: A monoclonal antibody to phencyclidine was developed, produced in mouse ascites fluid, and purified. The purification used only preparative-scale isoelectric focusing in the Rotofor and dialysis. In 4 h, 25% (4 mg) of the antibody from 10 ml of ascites fluid was purified to homogeneity while 63% of the total antibody was recovered. © 1988.
• Schoerlin, M. -., Mayersohn, M., Hoffmann, K., Ohnhaus, E. E., Dellenbach, M., Pfefen, J. -., & Guentert, T. W. (1988). Pharmacokinetics of moclobemide (Ro 11-1163) in patients with liver cirrhosis. Pharmacological Research Communications, 20(SUPPL. 4), 123-124.
• Schoerlin, M. P., Mayersohn, M., Hoevels, B., Eggers, H., Dellenbach, M., & Pfefen, J. P. (1988). Effect of food intake on the relative bioavailability of moclobemide (Ro 11-1163).. Journal of Neural Transmission, Supplement, 26, 115-121.
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  PMID: 3283288;Abstract: Twelve healthy adult volunteers received a single 100-mg tablet of moclobemide in an open-label crossover study designed to determine the influence of food on moclobemide absorption. Moclobemide was administered 30 min after a standard breakfast as well as under fasting conditions. Moclobemide absorption was rapid in the absence of food. Bioavailability parameters obtained when drug was taken 30 min after the meal suggested that the rate of absorption was slightly decreased in the presence of food (mean Tmax 0.71 h vs. 1.14 h), while the extent of absorption of moclobemide given with food was unaltered. The decreased absorption rate in the presence of food is not expected to be of clinical significance.
• Lopez-Anaya, A., & Mayersohn, M. (1987). Ascorbic and dehydroascorbic acids simultaneously quantified in biological fluids by liquid chromatography with fluorescence detection, and comparison with a colorimetric assay. Clinical Chemistry, 33(10), 1874-1878.
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  PMID: 3665043;
• Lopez-Anaya, A., & Mayersohn, M. (1987). Quantification of riboflavin, riboflavin 5′-phosphate and flavin adenine dinucleotide in plasma and urine by high-performance liquid chromatography. Journal of Chromatography B: Biomedical Sciences and Applications, 423(C), 105-113.
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  PMID: 3443641;Abstract: A high-performance liquid chromatographic method with fluorimetric detection for the quantification of riboflavin (RB), riboflavin 5′-phosphate (FMN), and flavin adenine dinucleotide (FAD) in plasma, whole blood, and urine is described. Under isocratic conditions with a reversed-phase column, the compounds are completely resolved and eluted within 9 min. Plasma proteins are precipitated with acetonitrile followed by shaking the aqueous phase with chloroform. Urine samples are diluted and injected directly. The reproducibility of this method for the quantification of RB in plasma has a between-day coefficient of variation of 6%. The application of this method is illustrated by analyzing plasma and urine samples from a human subject who received an intravenous dose of FMN equivalent to 25 mg of RB. © 1987.
• Mayersohn, M. (1987). Drug absorption.. Journal of Clinical Pharmacology, 27(9), 634-638.
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  PMID: 3316310;
• Navin, T. R., Dickinson, C. M., Adams, S. R., Mayersohn, M., & Juranek, D. D. (1987). Effect of azotemia in dogs on the pharmacokinetics of pentamidine. Journal of Infectious Diseases, 155(5), 1020-1026.
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  PMID: 3559276;Abstract: We used a new high-performance liquid-chromatography assay to study the pharmacokinetics of pentamidine isethionate given intravenously to 10 dogs before and after surgically induced renal failure. The presurgery peak serum concentration of pentamidine averaged 867 ng/ml and by 6 hr had falled to 30 ng/ml. After surgery the peak and 6-hr concentrations were 780 ng/ml and 28 ng/ml. Mean total body clearance of pentamidine before surgery was 46.7 ml/min per kg, of which only 2.0 ml/min per kg was due to renal clearance. After surgery, total body clearance was 40.0 ml/min per kg, even though renal clearance had fallen 80% - to 0.4 ml/min per kg. Two dogs with azotemia and two control dogs received 14 daily infusions of pentamidine. Kinetic parameters measured after the last dose were not significantly different from those after the first dose, and the amount of pentamidine recovered from tissues was similar for dogs with azotemia and controls. In summary, because renal clearance of pentamidine accounted for such a small proportion of total body clearance, none of the parameters measured was affected significantly by moderate azotemia.
• Schaaf, L. J., Campbell, S. C., Mayersohn, M. B., Vagedes, T., & Perrier, D. G. (1987). Influence of smoking and gender on the disposition kinetics of metoprolol. European Journal of Clinical Pharmacology, 33(4), 355-361.
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  PMID: 3443140;Abstract: The purpose of this study was to examine the influence of cigarette smoking and gender on the pharmacokinetics of metoprolol. Eighteen volunteers with no evidence of clinical disease each randomly received the following doses of metoprolol tartrate: 100 mg orally, 200 mg orally and 20 mg as a constant-rate intravenous infusion over 20 min. The only significant difference between smokers (S) and nonsmokers (NS) was that S had a larger steady-state volume of distribution (3.3 vs 2.5 l/kg). There were no differences in half-life, systemic clearance or bioavailability (f). No differences were observed between males (M) and females (FM) for any of the kinetic parameters examined. Systemic bioavailability varied markedly between subjects (range: 15 to 92%). In fifteen of the eighteen subjects, f was higher after the 200-mg dose compared to the 100-mg dose. These results suggest that metoprolol may be subject to saturable presystemic elimination and extend the previous observations of Johnsson et al. [1] who showed that f increased from 31% to 46% when doses were increased from 20 to 100 mg. However, the difference in f as the dose is increased is unlikely to be clinically significant since the mean difference is smaller than the variation in f among subjects. © 1987 Springer-Verlag.
• Schoerlin, M. -., Mayersohn, M., Korn, A., & Eggers, H. (1987). Disposition kinetics of moclobemide, a monoamine oxidase-A enzyme inhibitor: Single and multiple dosing in normal subjects. Clinical Pharmacology and Therapeutics, 42(4), 395-404.
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  PMID: 3665338;Abstract: The absorption and disposition kinetics of moclobemide (Ro 11-1163), a new reversible and preferential monoamine oxidase-A enzyme inhibitor, were examined in 12 normal male subjects. An intravenous infusion was administered before and after a 15-day multiple oral dosing regimen (100 mg t.i.d.). Plasma concentration-time data were obtained after each intravenous infusion, after the first oral dose, during two dosing intervals at steady state, and before the second daily dose on several days. The disposition values (percent coefficient of variation in parentheses) after the first and second intravenous infusions, respectively, were: clearance, 39.4 (15%) and 29.1 (12%) L/hr; elimination half-life, 1.60 (15%) and 2.00 (18%) hours; and volume of distribution at steady state, 84.3 (11%) and 80.7 (15%) L. The absolute oral bioavailability increased from 0.56 after the first oral dose to 0.86 and 0.90 after the first and second weeks of administration, respectively. The reduced metabolic, presumably hepatic, clearance may be the result of self-inhibition or metabolite inhibition of moclobemide clearance.
• Anaya, A. L., Mayersohn, M., Conrad, K. A., & Dimmitt, D. C. (1986). The influence of sucralfate on ibuprofen absorption in healthy adult males. Biopharmaceutics and Drug Disposition, 7(5), 443-451.
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  PMID: 3779035;Abstract: Sucralfate (Carafate®) is a new anti-ulcer agent the effects of which are mediated locally in the gastrointestinal tract. The use of this compound in conjunction with ulcerogenic drugs such as ibuprofen may represent a means of reducing gastrointestinal irritation. Combined oral therapy, however, requires evaluation of a potential interaction in absorption between those agents. The purpose of this study was to examine the influence of sucralfate coingestion on ibuprofen absorption. Twelve normal, healthy male subjects ingested a single oral 400 mg dose of ibuprofen alone or with sucralfate given as 1 g doses four times a day for 2 days prior to and during the study. Ibuprofen serum concentrations were measured for 12 hours following dosing. Parameters associated with rate of absorption (i.e. C(max), t(max), K(a)) were significantly altered in the presence of sucralfate (p < 0.05). In contrast, the relative bioavailability of ibuprofen was not significantly different between treatments (p > 0.05). Therefore, sucralfate does not alter the extent of ibuprofen absorption and would not be expected to change the response to that anti-inflammatory agent.
• Bliss, M., & Mayersohn, M. (1986). Liquid-chromatographic assay of cefamandole in serum, urine, and dialysis fluid. Clinical Chemistry, 32(1), 197-200.
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  PMID: 3940707;Abstract: We describe a 'high-performance' liquid-chromatographic assay for quantifying cefamandole in biological fluids from patients with renal impairment. Serum samples are deproteinized with acetonitrile, then extracted with dichloromethane; dialysis-fluid samples are injected directly; urine samples are diluted appropriately before injection onto the reversed-phase column. The mobile phase is a methanol/aqueous solution (31/69 by vol) containing 500 μL of phosphoric acid, 20 mmol of sodium sulfate, and 200 μL of triethylamine per liter, the mixture being adjusted to pH 6.0 with NaOH. Retention time for cefamandole is 12 min. Its peak is well resolved in highly contaminated samples from renally impaired subjects. The assay's selectivity, reproducibility (within-day and between-day CVs
• Bliss, M., Mayersohn, M., & Nolan, P. (1986). High-performance liquid chromatographic analysis of amiodarone and desethylamiodarone in serum. Journal of Chromatography B: Biomedical Sciences and Applications, 381(C), 179-184.
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  PMID: 3771717;
• Bliss, M., Mayersohn, M., Arnold, T., Logan, J., Michael, U. F., & Jones, W. (1986). Disposition kinetics of cefamandole during continuous ambulatory peritoneal dialysis. Antimicrobial Agents and Chemotherapy, 29(4), 649-653.
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  PMID: 3707113;PMCID: PMC180460;Abstract: Cefamandole disposition kinetics were examined in six male subjects with renal impairment who were undergoing continuous ambulatory peritoneal dialysis. Creatinine clearance values ranged from
• Campbell, S., Nolan Jr., P. E., Bliss, M., Wood, R., & Mayersohn, M. (1986). Stability of amiodarone hydrochloride in admixtures with other injectable drugs. American Journal of Hospital Pharmacy, 43(4), 917-921.
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  PMID: 3706337;Abstract: The stability of aminodarone hydrochloride in intravenous admixtures was studied. Amiodarone hydrochloride 900 mg was mixed with 500 mL of either 5% dextrose injection or 0.9% sodium chloride injection in polyvinyl chloride or polyolefin containers; identical solutions were also mixed with either potassium chloride 20 meq, lidocaine hydrochloride 2000 mg, quinidine gluconate 500 mg, procainamide hydrochloride 2000 mg, verapamil hydrochloride 25 mg, or furosemide 100 mg. All admixtures were prepared in triplicate and stored for 24 hours at 24°C. Amiodarone concentrations were determined using a stability-indicating high-performance liquid chromatographic assay immediately after admixture and at intervals during storage. Each solution was visually inspected and tested for pH. Amiodarone concentrations decreased less than 10% in all admixtures except those containing quinidine gluconate in polyvinyl chloride containers. The only visual incompatibility observed was in admixtures containing quinidine gluconate and 5% dextrose injection. In most solutions pH either decreased slightly or remained unchanged. Amiodarone hydrochloride is stable when mixed with either 5% dextrose injection or 0.9% sodium chloride injection in polyvinyl chloride or polyolefin containers alone or with potassium chloride, lidocaine, procainamide, verapamil, or furosemide and stored for 24 hours at 24°C. Amiodarone should not be mixed with quinidine gluconate in polyvinyl chloride containers.
• D'Angio, R., Mayersohn, M., Conrad, K. A., & Bliss, M. (1986). Cimetidine absorption in humans during sucralfate coadministration. British Journal of Clinical Pharmacology, 21(5), 515-520.
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  PMID: 3755052;PMCID: PMC1401033;Abstract: Cimetidine absorption after a single 300 mg oral dose was evaluated in six normal subjects in the absence or presence of sucralfate. Sucralfate was ingested four times a day for 2 days prior to and for two additional doses on the day of cimetidine ingestion. Sucralfate coadministration had no statistically significant influence on the rate or extent of cimetidine absorption.
• Johnson, S. L., Mayersohn, M., & Conrad, K. A. (1986). Xylose disposition in humans as a function of age. Clinical Pharmacology and Therapeutics, 39(6), 697-702.
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  PMID: 3709034;Abstract: D-Xylose disposition was examined in 24 healthy men between 32 and 85 years of age. Xylose was administered as a 5 gm iv infusion and as a 25 gm po solution. Serum xylose concentrations and urinary excretion of intact xylose were determined. There were statistically significant inverse relationships with age for each of the following parameters after intravenous infusion: elimination rate constant (r2=0.71); systemic clearance (r2=0.66); renal clearance (r2=0.65); and nonrenal clearance (r2=0.35). Similar inverse relationships were found after oral dosing for the elimination rate constant (r2=0.69) and renal clearance (r2=0.54). There was no significant age relationship for the apparent volume of distribution or the steady-state volume of distribution. The percentage of the oral and intravenous dose recovered in urine up to 5 hours after dosing was significantly and inversely correlated with age. The implications of the latter finding are discussed with regard to the interpretation of the xylose tolerance test used to assess gastrointestinal absorptive capacity.
• Jones, W. N., Kern, K. B., Rindone, J. P., Mayersohn, M., Bliss, M., & Goldman, S. (1986). Digoxin-diltiazem interaction: A pharmacokinetic evaluation. European Journal of Clinical Pharmacology, 31(3), 351-353.
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  PMID: 3792433;Abstract: The pharmacokinetics of digoxin were studied before and after a 2 week course of diltiazem, 30 mg four times daily, in 7 healthy volunteers. Each subject received an IV dose of digoxin before starting diltiazem and again on day 15 of the study. Diltiazem was continued until all sera and urine were collected. During the control and diltiazem phases, respectively, the terminal elimination rate constants were 0.0231±0.007 h-1 and 0.0254±0.007 h-1, the volumes of distribution were 10.5±3.95 l/kg and 10.2±3.26 l/kg, and the total body clearances were 3.72±0.78 ml·min-1·kg-1 and 4.09±0.94 ml·min-1·kg-1. None of these pharmacokinetic parameters of digoxin were significantly different before or during diltiazem administration. Overall, there does not appear to be an interaction between digoxin and diltiazem. © 1986 Springer-Verlag.
• Owens, S. M., & Mayersohn, M. (1986). Modulation of phencyclidine (PCP) pharmacokinetics with PCP-specific fab fragments. NIDA Research Monograph Series, NO. 64, 112-126.
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  PMID: 3086729;Abstract: A promising technique for detoxification of certain drugs is the use of drug-specific antibody fragments (Fab, the antigen-binding fragment of IgG). This type of treatment has been shown to reverse digoxin and digitoxin toxicity rapidly in both animals and humans. The purpose of this paper is to discuss the important factors in the use of immunotherapy for treating PCP toxicity and to present preliminary data on the effects of anti-PCP Fab fragments on PCP pharmacokinetics in dogs.
• Owens, S. M., & Mayersohn, M. (1986). Phencyclidine-specific Fab fragments alter phencyclidine disposition in dogs. Drug Metabolism and Disposition, 14(1), 52-58.
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  PMID: 2868866;Abstract: High affinity antibodies (K0 = 3 x 109 M-1) against the widely abused drug phencyclidine (PCP) were produced in goats and then purified and extensively characterized for use in in vivo pharmacokinetic studies. An iv dose of 3H-PCP was administered to three dogs, followed 2 hr later by an equimolar dose of PCP-specific antigen-binding fragments (Fab). Within 10 min after Fab administration, the concentration of PCP in the serum had increased 17-56-fold in the three dogs. The Fab administration also produced a 10-fold decrease in volume of distribution and in systemic and renal clearances. The concentration of PCP metabolites decreased for a period of time after Fab administration. Equilibrium dialysis studies showed that the percentage of unbound PCP changed from about 50% before Fab administration to
• Woodworth, J. R., Mayersohn, M., & Owens, S. M. (1986). Disposition kinetics of the monohydroxy metabolites of phencyclidine in the dog. Journal of Pharmacology and Experimental Therapeutics, 238(3), 900-904.
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  PMID: 3746667;Abstract: The monohydroxy metabolites of phencyclidine (PCP) have been suggested to contribute to the pharmacologic activity of PCP, and perhaps account for its prolonged action. The disposition kinetics of the monohydroxy metabolites of PCP were examined in dogs. Intravenous doses of the piperidine-hydroxylated metabolite (PCHP) and the trans- and cis-forms of the cyclohexylhydroxylated metabolite (trans-PPC and cis-PPC) were each administered to three dogs. The elimination half-life of each metabolite was short, with harmonic mean values of 1.29, 0.98 and 0.92 hr for PCHP, trans-PPC and cis-PPC, respectively. The compounds had large volumes of distribution, with average values of 6.7, 4.7 and 4.4 liters/kg for PCHP, trans-PPC and cis-PPC, respectively. Systemic clearances were high for each compound (51.9, 50.9 and 54.2 ml/min/kg for PCHP, trans-PPC and cis-PPC, respectively), but renal clearances were low (average values ranged from 2 to 8% of systemic clearance), suggesting that these metabolites undergo further metabolism. Analysis of acid-hydrolyzed serum and urine samples indicated that all three compounds were conjugated and that these conjugates were the primary metabolites. The conjugated metabolites exhibited elimination half-lives longer than the parent compounds after administration of the monohydroxy forms and after PCP dosing. The disposition of these metabolites suggest that these compounds are not produced in sufficient quantities or do they exhibit pharmacokinetic behavior which would be consistent with the prolonged effects from PCP.
• Achari, R., & Mayersohn, M. (1985). Modified liquid-chromatographic method for creatinine determination: a rebuttal.. Clinical Chemistry, 31(11), 1918-1919.
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  PMID: 4053375;
• Johnson, S. L., & Mayersohn, M. (1985). Comparison of fitting methods for the analysis of plasma concentration-time data resulting from constant rate intravenous infusion. Biopharmaceutics and Drug Disposition, 6(3), 313-323.
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  PMID: 4041557;Abstract: Plasma concentration-time data resulting from constant rate intravenous infusion may be analysed in two ways: 1. Samples may be collected both during and after infusion and fit to an infusion model. 2. Samples may be collected after infusion is complete and the data may be fit as an i.v. bolus. The purpose of this study was to contrast the two fitting procedures in terms of the accuracy of the parameter values obtained. Concentration-time data were computer-generated with the introduction of random error to simulate the disposition profiles of two model drugs. The results of these simulations indicate that satisfactory values for area-dependent parameters may be obtained without fitting data during the infusion phase. The exception to this is the apparent steady-state volume whose values become less accurate with longer infusion times. The parameters most affected by ignoring data points in the infusion phase are the central volume of distribution, and the coefficient and disposition rate constant associated with the initial, rapid phase of disposition. The equation which describes the entire concentration-time profile provides the most accurate parameter estimates of the model equation. In addition, we also describe the influence of the fitting method on the intercompartmental transfer rate constants.
• Johnson, S. L., Mayersohn, M., & Conrad, K. A. (1985). Gastrointestinal absorption as a function of age: Xylose absorption in healthy adults. Clinical Pharmacology and Therapeutics, 38(3), 331-335.
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  PMID: 4028629;Abstract: Xylose oral absorption was examined in 24 healthy male subjects ranging in age from 32 to 85 years. Absorption was evaluated from xylose plasma concentration-time data after administration of a 25 gm po or a 5 gm iv dose. There was no relationship between various estimates of the rate of absorption and age. The absolute oral bioavailability or the extent of xylose absorption showed no relationship to age in our population. In contrast with previous suggestions, xylose absorption does not decline with age. General statements of decreased gastrointestinal absorption efficiency as a function of age may not be correct. © 1985.
• Mayersohn, M., Owens, S. M., Anaya, A. L., Bliss, M., & Achari, R. (1985). 4-Methylpyrazole disposition in the dog: Evidence for saturable elimination. Journal of Pharmaceutical Sciences, 74(8), 895-896.
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  PMID: 4032277;
• Woodworth, J. R., Owens, S. M., & Mayersohn, M. (1985). Phencyclidine (PCP) disposition kinetics in dogs as a function of dose and route of administration. Journal of Pharmacology and Experimental Therapeutics, 234(3), 654-661.
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  PMID: 4032285;Abstract: Phencyclidine (PCP) disposition kinetics has been examined in dogs as a function of dose and after i.v. and p.o. administration. Intravenous doses ranged from a tracer quantity of [3H]PCP to 5 mg/kg of unlabeled PCP. The elimination half-life of intact PCP was relatively short with harmonic mean values of 2.7, 5.4 and 3.9 hr for the tracer, 1- and 5-mg/kg doses, respectively. In contrast, measurement of total radioactivity gave a much longer half-life (35-52 hr) suggesting slower metabolite elimination. The drug has a large apparent volume of distribution (weighted mean of 20 liters/kg) and a systemic clearance (which is primarily metabolic) that approaches estimates of liver blood flow in the dog. Renal clearance of intact PCP represents a small fraction of total clearance. Percentage of the [3H]PCP dose recovered as total radioactivity was 49% in urine and 12% in feces. Several metabolites of PCP were determined in urine and they account for about 30% of the dose with the aminopentanoic acid derivative being present in the greatest amount. One of the hydroxylated metabolites is present in cis- and trans-forms, with the latter predominating. Three animals received an i.v. dose of [3H]PCP and a p.o. dose of unlabeled PCP at the same time to determine absolute bioavailability. Approximately 25% of the dose is absorbed intact. The p.o. (intrinsic) clearance of PCP is about four times greater than systemic clearance suggesting a blood flow-dependence in clearance and substantial first-pass hepatic metabolism.
• Achari, R., & Mayersohn, M. (1984). Analysis of 4-methylpyrazole in plasma and urine by gas chromatography with nitrogen-selective detection. Journal of Pharmaceutical Sciences, 73(5), 690-692.
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  PMID: 6737245;Abstract: A simple, sensitive, and specific gas chromatographic method for the quantitation of 4-methylpyrazole in plasma and urine is described. Samples containing 4-methylpyrazole, with 3-methylpyrazole as the internal standard, are extracted into ether and the concentrated ethereal extracts are chromatographed on a Carbowax 20M column using nitrogen-selective detection. Standard curves are linear and reproducible over the range of 25-1000 ng/mL for plasma and 0.5-5 μg/mL for urine. Recovery of 4-methylpyrazole is complete from plasma and urine, and the overall between-day coefficient of variation is within 6.0%. No interference is observed from the extractive constituents of plasma and urine. The assay method is suitable for an examination of 4-methylpyrazole disposition in animals and humans.
• Conrad, K. A., Mayersohn, M., & Bliss, M. (1984). Cimetidine does not alter ibuprofen kinetics after a single dose. British Journal of Clinical Pharmacology, 18(4), 624-626.
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  PMID: 6487504;PMCID: PMC1463611;Abstract: Cimetidine doet not slow the disappearance of ibuprofen from the serum after a single dose in healthy male volunteers. This suggests that no change in ibuprofen dosing is necessary when cimetidine is co-administered.
• Johnson, S. L., & Mayersohn, M. (1984). Quantitation of xylose from plasma and urine by capillary column gas chromatography. Clinica Chimica Acta, 137(1), 13-20.
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  PMID: 6421511;Abstract: A specific and sensitive assay for quantitation of xylose from plasma and urine has been developed. Following a clean-up procedure, plasma (0.1 ml) or urine (0.2 ml) samples are concentrated and undergo two sequential derivatization steps. A methyloxime derivative is formed initially, followed by trimethylsilylation of all hydroxyl groups. The derivatized samples are quantitated by capillary column gas chromatography using flame ionization detection. Xylose and the internal standard (2-deoxy-d-ribose) have retention times of 6.5 and 5.2 min, respectively. Other monosaccharides (e.g. ribose, arabinose) do not interfere with the assay. Standard curves are linear and reproducible over a concentration range of 10-200 mg/l for plasma and 100-2000 mg/l for urine. The within-day and day-to-day percentage coefficients of variation were less than 5 and 9%, respectively, for plasma and urine. © 1984.
• Johnson, S. L., Bliss, M., Mayersohn, M., & Conrad, K. A. (1984). Phloroglucinol-based colorimetry of xylose in plasma and urine compared with a specific gas-chromatographic procedure. Clinical Chemistry, 30(9), 1571-1574.
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  PMID: 6467574;Abstract: A commonly used method for xylose has several disadvantages, including use of thiourea which is a carcinogen. We examined an alternative colorimetric method in which phloroglucinol (1,3,5-trihydroxybenzene) is the chromogenic reagent and compared it with a specific gas-chromatographic procedure for use with blood and urine samples from subjects receiving xylose either orally or intravenously. Results by these methods correlated well, both for plasma (r2 = 0.97) and urine (r2 = 0.99). At concentrations >50 mg/L for plasma (slope = 1.005) and >350 mg/L for urine (slope = 0.99) the slopes were not significantly different from 1 or the intercepts different from zero. We recommend this method as a safer and more expedient alternative to the method currently used.
• Woodworth, J. R., Mayersohn, M., & Owens, S. M. (1984). Quantitative analysis of phencyclidine and metabolites by capillary column gas chromatography. Journal of Analytical Toxicology, 8(1), 2-6.
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  PMID: 6708471;Abstract: A sensitive capillary gas chromatography (GC) procedure was developed for the analysis of phencyclidine (PCP), two of its monohydroxy-metabolites, and a recently identified pentanoic acid metabolite. Two separate, but sequential, integrated extraction techniques were necessary to isolate all of the compounds from a 1.0-mL biological sample. Two GC techniques were necessary to analyze all the compounds; both methods used a capillary column and a nitrogen phosphorus detector (NPD). The first procedure permitted isolation and quantitation of PCP and two monohydroxy-metabolites. A second extraction of the biological samples permitted measurement of the pentanoic acid metabolite. The analytical methods illustrate good reproducibility based on within-day and day-to-day variation. Serum and urine samples were analyzed from a dog administered PCP to illustrate the utility of this procedure.
• Achari, R., Mayersohn, M., & Conrad, K. A. (1983). HPLC analysis of creatinine in human plasma and urine. Journal of Chromatographic Science, 21(6), 278-281.
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  PMID: 6874876;Abstract: A simple, rapid, reproducible HPLC method is described for the analysis of creatinine in human plasma and urine. Creatinine is isolated from plasma proteins prior to HPLC analysis by ultrafiltration using a micropartition system. The technique requires only 0.2 ml of plasma and the recovery of creatinine is complete. Results from the HPLC analysis are compared with those from an automated (colorimetric) analysis. The retention time of creatinine is 2.6 min.
• Goldman, S., Hager, W. D., Olajos, M., Perrier, D., & Mayersohn, M. (1983). Effect of the ouabain-quinidine interaction of left ventricular and left atrial function in conscious dogs. Circulation, 67(5), 1054-1058.
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  PMID: 6831670;Abstract: The effect of the ouabain-quinidine interaction was examined in 10 conscious dogs. Left ventricular (LV) pressure, LV dP/dt, LV diameter and left atrial (LA) diameter were measured with high-fidelity micromanometers and sonomicrometer crystals. Ouabain, 0.025 mg/kg, significantly (p < 0.05) increased LV dP/dt, LV and LA fractional shortening and LV and LA velocity of circumferential fiber shortening (Vcf). In a separate experiment, quinidine was administered as a bolus dose, 3.85 mg/kg, followed by an infusion, 0.28 mg/kg/min. This resulted in steady-state quinidine concentrations that produced no change in wall motion or hemodynamics. When ouabain was given 1 hour into the quinidine infusion, only LV dP/dt increased significantly (p < 0.05). Ouabain alone increased LV dP/dt 26.4 ± 3.5%, whereas ouabain during the quinidine infusion increased it by 9.5 ± 2.3%. Similar differences were seen in the response to ouabain in the absence and presence of quinidine: LV Vcf, 22.4 ± 4.9% vs 6.0 ± 2.1%, LV fractional shortening, 23.1 ± 4.6% vs 5.8 ± 2.1%, LA Vcf, 22.7 ± 5.9 vs 4.6 ± 2.0% and LA fractional shortening, 21.8 ± 7% vs 7.8 ± 3.3%. Thus, in the presence of quinidine the increase in intropy usually seen with ouabain was markedly attenuated. These data suggest that the quinidine-induced increase in digoxin serum concentrations is accompanied by a decrease in the contractile response of the heart to digoxin.
• Kogan, F. J., Sampliner, R. E., Mayersohn, M., Kazama, R. M., Perrier, D., Jones, W., & Michael, U. F. (1983). Cimetidine disposition in patients undergoing continuous ambulatory peritoneal dialysis. Journal of Clinical Pharmacology, 23(5-6), 252-256.
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  PMID: 6875024;Abstract: Cimetidine disposition was determined in six patients undergoing continuous ambulatory peritoneal dialysis to ascertain the need for modification of conventional dosing regimens. Blood, dialysis fluid, and urine were collected for 48 hours after administration of a single intravenous dose of cimetidine. The following values were obtained: elimination half-life, 4.3 hours; systemic or total body clearance, 191 ± 55 ml/min; and dialysis clearance, 4.2 ± 3.1 ml/min. Approximately 2% of a cimetidine dose is removed by dialysis indicating that there is no need to adjust the conventional renal failure dosing regimen in patients undergoing continuous ambulatory peritoneal dialysis.
• Mayersohn, M., Conrad, K. A., & Achari, R. (1983). Creatinine clearance and urine flow.. Drug Intelligence and Clinical Pharmacy, 17(2), 131-.
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  PMID: 6825568;
• Mayersohn, M., Conrad, K. A., & Achari, R. (1983). The influence of a cooked meat meal on creatinine plasma concentration and creatinine clearance. British Journal of Clinical Pharmacology, 15(2), 227-230.
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  PMID: 6849756;PMCID: PMC1427867;Abstract: The influence of a meal containing cooked meat (225 g) on creatinine plasma concentration, creatinine urinary excretion and creatinine clearance was determined in six healthy male subjects. The meat meal produced an average 52% increase in creatinine plasma concentration within 1.5 to 3.5 h after ingestion. The 24 h area under the creatinine plasma concentration-time curve increased by about 19%. Urinary creatinine excretion during 24 h increased by an average of 13%. Creatinine clearance was not altered in response to the meal of cooked meat.
• Owens, S. M., Mayersohn, M., & Woodworth, J. R. (1983). Phencyclidine blood protein binding: Influence of protein, pH and species. Journal of Pharmacology and Experimental Therapeutics, 226(3), 656-660.
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  PMID: 6887006;Abstract: We studied the influence of protein, pH and species on phencyclidine (PCP) protein binding. PCP binding to dog serum was unaffected by high concentrations of PCP and metabolites. The percentage of unbound PCP in pooled human serum and plasma specimens and pooled dog serum specimens was (mean ± SD); 48.3 ± 2.5; 42.5 ± 1.8; and 43.3 ± 1.9%, respectively. The percentage of unbound PCP in human serum albumin (HSA), 81.2 ± 2.0%, was constant over the physiological HSA concentration range (3.5-5.5 g/dl). The binding of PCP to α1-acid glycoprotein (α1-AGP) increased with increasing α1-AGP concentration (50-200 mg/dl). The binding to HSA or α1-AGP separately did not account for the binding found in whole serum or plasma specimens. However, when a constant concentration of HSA (4.5 g/dl) was added to varying concentrations of α1-AGP, the PCP binding increased dramatically and was similar to the binding found in human serum specimens. The association constant in the presence of both proteins (7.72 x 104 M-1) was 4.4 times greater than the association constant for α1-AGP alone (1.74 x 104 M-1). This suggested an interaction between the proteins which resulted in enhanced PCP binding. The percentage of unbound PCP increased with decreasing pH in both dog serum and human serum specimens. This change could have possible effects on PCP distribution and elimination. The PCP blood to plasma ratio was 0.94 in pooled human heparinized blood and 1.25 in pooled dog heparinized blood. Neither species showed PCP concentration-dependent partitioning.
• Woodworth, J. R., Owens, S. M., & Mayersohn, M. (1983). Phencyclidine (PCP) disposition kinetics in dogs: Preliminary observations. Research Communications in Substances of Abuse, 4(1), 49-58.
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  Abstract: Phencyclidine (PCP) disposition kinetics was examined in 5 dogs after administration of 1 mg/kg doses as an intravenous bolus. PCP undergoes a pronounced distributive phase and has a large volume of distribution (ca 25 L/kg). The elimination half-life is highly variable, ranging from 2.6 to 13.5 hours. Total body clearance is a large value (ca 45 ml/min/kg), whereas renal clearance (determined in 2 dogs) represents only a small percentage of total clearance (0.7-1.9%).
• Appelbaum, S. J., Mayersohn, M., Dorr, R. T., & Perrier, D. (1982). Allopurinol kinetics and bioavailability - Intravenous, oral and rectal administration. Cancer Chemotherapy and Pharmacology, 8(1), 93-98.
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  PMID: 7094203;Abstract: Six normal, healthy adult males received a single dose of allopurinol intravenously, orally in the form of a commercial tablet, and rectally in the form of an extemperaneously prepared suppository (either in a cocoa butter or in polyethylene glycol base). Plasma allopurinol and oxipurinol concentrations were measured over a period of at least 60 h. The following mean (±SD) values were obtained from the intravenous allopurinol experiment: clearance, 9.62±3.49 ml · kg-1 · min-1; Vd, 1.61±0.74 l/kg; t1/2, 1.62 h. Oxipurinol had a mean t1/2 of 16.90 h. The absolute systemic bioavailability of the oral tablet was 67%±23%, while the allopurinol rectal suppositories produced no measurable plasma concentrations of allopurinol or oxipurinol in any of the subjects. Current use of rectal dosage forms as an adjunct in cancer chemotherapy should therefore be re-examined. © 1982 Springer-Verlag.
• Bikin, D., Conrad, K. A., & Mayersohn, M. (1982). Lack of influence of caffeine and aspirin on lithium elimination. Clinical Research, 30(2), 249A.
• Jung, D., Mayersohn, M., Perrier, D., Calkins, J., & Saunders, R. (1982). Thiopental disposition as a function of age in female patients undergoing surgery. Anesthesiology, 56(4), 263-268.
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  PMID: 7065434;Abstract: The effect of age on the disposition kinetics of thiopental was studied in 22 lean female patients having a body mass index (weight (kg)/height(m)2) less than 30 and whose age ranged between 25 to 83 years. Patients underwent primarily abdominal surgery. A strong positive correlation between age and the apparent volumes of distribution, Vβ and V(ss), was found (P
• Jung, D., Mayersohn, M., Perrier, D., Calkins, J., & Saunders, R. (1982). Thiopental disposition in lean and obese patients undergoing surgery.. Anesthesiology, 56(4), 269-274.
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  PMID: 7065435;Abstract: The effect of obesity on the disposition kinetics of thiopental was studied in seven morbidly obese (age 25 to 46 years) and eight age-matched lean patients (age 25 to 43 years), undergoing primarily abdominal surgery. Based upon total (bound + free) thiopental concentrations, the average (+/-SD) volumes of distribution in the terminal disposition phase and at steady-state (V beta and V ss) were significantly larger in the obese (7.94 +/- 4.55 1/kg and 4.72 +/- 2.73 1/kg, respectively) than in the age-matched lean patients (1.95 +/- 0.63 1/kg and 1.40 +/- 0.46 1/kg, respectively). Clearance of total thiopental, normalized for total body weight was not significantly different between the obese (0.18 +/- 0.081 . h-1 . kg-1) and lean patients (0.21 +/- 0.06 1 . h-1 . kg-1). However, total body clearance not normalized for total body weight was significantly larger in the obese (24.98+/- 14.87 1/h) than in the lean patients (11.86 +/- 3.66 1/h). The elimination half-life of thiopental was significantly longer in the obese (27.85 h) than in the lean patients (6.33 h) and this difference was primarily a function of a larger apparent volume of distribution for thiopental. The unbound fraction of thiopental in serum (range, 17.8 per cent to 27.6 per cent) was not correlated with the degree of obesity. The most appropriate means of comparing intrinsic metabolizing capacity (i.e., normalized vs. non-normalized for weight) between lean and obese subjects remains unresolved.
• Mayersohn, M. (1982). The 'Xylose test' to assess gastrointestinal absorption in the elderly: A pharmacokinetic evaluation of the literature. Journals of Gerontology, 37(3), 300-305.
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  PMID: 7069153;Abstract: A pharmacokinetic evaluation has been made of the literature that has examined xylose absorption as a function of age. Urinary xylose recovery during a 5-hour collection declines with age after oral and intravenous dosing. Calculated values for xylose renal clearance and elimination rate constant display a similar dependence upon age. The ratio of urinary recoveries after oral compared with intravenous dosing remains constant up to age 65 years but decreases after 70 years. Age appears to explain most of the variation associated with the above parameters. This analysis supports the suggestion made previously by several investigators that the xylose test as currently used to assess absorption in the elderly has not been properly interpreted.
• Owens, S. M., Woodworth, J., & Mayersohn, M. (1982). Radioimmunoassay for phencyclidine (PCP) in serum. Clinical Chemistry, 28(7), 1509-1513.
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  PMID: 7083566;Abstract: This accurate, sensitive radioimmunoassay for determining phencyclidine concentrations in serum specimens involves the use of anti-phencyclidine sera, 0.1 mL of serum specimen, an iodinated tracer, and a solid-phase separation. Phencyclidine metabolites do not show significant cross reactivity, but several phencyclidine analogs do cross react. Within-run coefficients of variation for human and dog serum ranged from 2.5 to 13% for concentrations from 2.0 to 500 μg/L. Day-to-day coefficients of variation for human and dog serum ranged from 4.3 to 16.7% for concentrations ranging from 2.0 to 90.0 μg/L. The sensitivity of the radioimmunoassay is < 0.5 μg/L. Thirty serum specimens from two dogs given 1 mg of phencyclidine per kilogram body weight were analyzed by radioimmunoassay and a gas-chromatographic method. Nonparametric statistical comparison and linear regression showed that results from the two procedures correlate well (r2 = 0.952). Concentration-time data from the two dogs are presented to illustrate the utility of the radioimmunoassay for examining phencyclidine disposition.
• Perrier, D., & Mayersohn, M. (1982). Determination of a loading dose for a multiple dosing regimen.. Drug Intelligence and Clinical Pharmacy, 16(10), 780-781.
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  PMID: 7140517;
• Perrier, D., & Mayersohn, M. (1982). Noncompartmental determination of the steady-state volume of distribution for any mode of administration. Journal of Pharmaceutical Sciences, 71(3), 372-373.
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  PMID: 7069605;
• Yung, S., Mayersohn, M., & Robinson, J. B. (1982). Ascorbic acid absorption in humans: A comparison among several dosage forms. Journal of Pharmaceutical Sciences, 71(3), 282-285.
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  PMID: 7069582;
• Goldman, S., Olajos, M., Pieniaszek, H., Perrier, D., Mayersohn, M., & Morkin, E. (1981). Beta adrenergic blockade with propranolol in conscious euthyroid and thyrotoxic calves: Dosage requirements and effects on heart rate and left ventricular performance. Journal of Pharmacology and Experimental Therapeutics, 219(2), 394-399.
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  PMID: 7288628;Abstract: The effects of acute beta adrenergic blockade were studied in nine calves which had been instrumented with sonomicrometer crystals and pressure transducers before and after treatment with thyroxine (200 μg/kg) for 14 days. The adequacy of beta adrenergic blockade was determined using graded doses of isoproterenol. The results indicated that beta adrenergic blockade had no significant effect on heart rate, left ventricular dimensions or contractile performance in either thyroid state, However, the average dose of propranolol required to achieve beta adrenergic blockade was increased two to three times by thyroxine treatment. Consequently, the kinetics of propranolol disposition were determined in nine animals after a single i.v. dose of the drug. Also, propranolol was administered to four animals by continuous i.v. infusions at graded dosages to produce a range of serum concentrations in each animal. The amount of isoproterenol required to increase the heart rate by 25 beats/min was determined at each dosage level. It was found that in thyrotoxic animals two to three times higher serum propranolol concentrations were required to block challenge doses of isoproterenol. This could not be explained by changes in the disposition of propranolol. The possibility that there are larger numbers of functionally inactive (uncoupled) beta adrenergic receptors in thyrotoxic myocardium is discussed.
• Hager, W. D., Mayersohn, M., & Graves, P. E. (1981). Digoxin bioavailability during quinidine administration. Clinical Pharmacology and Therapeutics, 30(5), 594-599.
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  PMID: 7297019;Abstract: Digoxin serum concentration rises in the presence of quinidine. To determine whether quinidine alters digoxin bioavailability, six subjects received 1.0 rag of digoxin intravenously alone and by mouth on alternate weeks during steady-state oral quinidine administration. The area under the digoxin concentration: tune curves (AUC) and the amount of digoxin excreted in the urine (Xuχ) were determined for the 96 hr after each of the four experiments. Values for digoxin bioavailability relative to the corresponding intravenous study in the absence and presence of quinidine were (±S.D.) 73.5 ± 8.6% and 79.5 ± 22.6% (P > 0.05),for serum and 69.8 ± 6.8% and 70.2 ± 10.5% (P > 0.05), for urine. There was no difference in the steady-state quinidine serum concentration during the 4 clays after intravenous and oral digoxin. We conclude that quinidine does not alter digoxin bioavailability and therefore that altered absorption does not explain the rise in digoxin serum concentration in the presence of quinidine. © 1981.
• Hager, W., Pieniaszek Jr., H. J., Perrier, D., Mayersohn, M., & Goldberger, V. (1981). Assessment of beta blockade with propranolol. Clinical Pharmacology and Therapeutics, 30(3), 283-290.
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  PMID: 6115730;Abstract: Each of seven subjects received on a weekly basis placebo or 10, 20, 40, 80, or 160 mg propanolol orally four times daily. The effect of propranolol on the resting heart rate and the heart rate response to the Valsalva maneuver, tilt, isoproterenol, and maximal exercise were measured. Coefficients of determination were calculated from the individual dose-response curves. The results indicate that the resting heart rate and the tachycardiac response to the Valsalva maneuver and tilt cannot be used to estimate beta blockade. Propranolol concentrations correlated well (mean r2 = 0.80) with the isoproterenol dose ratio minus one, but isoproterenol challenges appear clinically inapplicable. Reduction in maximal exercise tachycardia correlated best with propranolol concentrations (mean r2 = 0.89) but, to the extent that exercise could not be performed, there was no reliable way of clinically documenting beta blockade and only the serum concentration of propranolol was available as an indicator of appropriate therapy. © 1981.
• Jung, D., Mayersohn, M., & Perrier, D. (1981). Gas-chromatographic assay for thiopental in plasma, with use of a nitrogen-specific detector. Clinical Chemistry, 27(1), 113-115.
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  PMID: 7449092;Abstract: An accurate, sensitive, and specific gas-liquid-chromatographic procedure is described for determining concentrations of thiopental in human plasma. After a double extraction of 0.2 or 1.0 mL of plasma containing phenobarbital as an internal standard, thiopental and the internal standard are derivatized in a polar non-aqueous solvent system with iodomethane. The reaction mixture is then evaporated, the residue reconstituted with ethyl acetate, and 20 μL injected into a 3% OV-17 column of a gas chromatograph equipped with a nitrogen-phosphorus detector. Linearity and reproducibility over the concentration range 25 μg/L to 10 mg/L in plasma are excellent. The sensitivity and wide range of linearity exhibited by this method permit thorough characterization of the disposition of thiopental after the usual induction doses of 3-4 mg/kg of body weight.
• Jung, D., Mayersohn, M., & Perrier, D. (1981). The 'ultra-free' ultrafiltration technique compared with equilibrium dialysis for determination of unbound thiopental concentrations in serum. Clinical Chemistry, 27(1), 166-168.
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  PMID: 7449102;Abstract: We compare a new ultrafiltration technique, involving a unique Millipore membrane, with the classical method of equilibrium dialysis for determining the fraction of thiopental not bound to serum proteins. This fraction, as determined by equilibrium dialysis at 37°C, ranged between 12 and 16% for total concentrations of 50 μg/L to 10 mg/L of serum. In contrast, ultrafiltration at 37°C yielded a 49% higher value for unbound thiopental: 26.3 (SD 2.6)%. Determined at room temperature (24°C), there was no statistically significant difference for results by the two methods: 14.2 and 15.9%, respectively. The discrepancy between results at 37°C may partly be explained by serum proteins penetrating the Ultra-Free® filter. For the routine clinical measurement of unbound drug concentrations, the ultrafiltration membrane at room temperature appears to be sufficiently accurate and less time- consuming than equilibrium dialysis.
• Mayersohn, M. (1981). Area under the plasma concentration-time curve resulting from constant-rate drug input. Journal of Pharmaceutical Sciences, 70(11), 1296-1297.
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  PMID: 7299684;
• Mayersohn, M., Calkins, J. M., & Perrier, D. G. (1981). Thiopental kinetics in obese surgical patients. Anesthesiology, 55(3 Suppl.), A178.
• Yung, S., Mayersohn, M., & Robinson, J. (1981). Ascorbic acid absorption in man: influence of divided dose and food. Life Sciences, 28(22), 2505-2511.
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  PMID: 7253837;Abstract: The urinary recovery of ascorbic acid (AA) was examined in 3 subjects when the vitamin was given as a single 1 g dose in solution (control), as divided doses in solution (0.125 g every 15 min. for 8 doses) and as a 1 g solution after eating a meal high in fat content. The divided dose and after-meal treatments produced a significant increase in AA absorption compared to the corresponding control experiment, 72% and 69% increase, respectively. Absorption appears to be delayed and prolonged under the latter conditions. These results are consistent with the suggestion that the vitamin is absorbed by a specialized process at sites high in the small intestine. © 1981.
• Fenster, P., Perrier, D., Mayersohn, M., & Marcus, F. I. (1980). Kinetic evaluation of the propranoloi-quinidine combination. Clinical Pharmacology and Therapeutics, 27(4), 450-453.
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  PMID: 7357801;Abstract: The kinetics of quinidine and propranolol, administered singly and in combination, were evaluated in 5 healthy subjects. The orally administered doses resulted in plasma concentrations within the therapeutic range. For each drug the average steady-state plasma concentration, maximal plasma concentration, and time of maximum plasma concentration were not altered by the presence of the other drug. This study shows no kinetic interaction between quinidine and propranolol in normal subjects. © 1980.
• Giardina, E. G., Fenster, P. E., Bigger Jr., J. T., Mayersohn, M., Perrier, D., & Marcus, F. I. (1980). Efficacy, plasma concentrations and adverse effects of a new sustained release procainamide preparation. American Journal of Cardiology, 46(5), 855-862.
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  PMID: 6159783;Abstract: To assess the efficacy, plasma drug concentrations and adverse effects of a new sustained release preparation of procainamide, 33 patients with heart disease were studied in an acute dose-ranging protocol and a chronic treatment protocol. Patients initially received a daily dose of 3 g of sustained release procainamide; this dose was increased by 1.5 g daily until ventricular premature depolarizations were suppressed by 75 percent or more, adverse drug effects occurred or a total daily dose of 7.5 g of sustained-release procainamide was reached. Twenty-five patients (76 percent) had at least a 75 percent reduction (range 75 to 100 percent [mean ± standard deviation 91 ± 8.2]) in ventricular premature depolarization frequency at a dosage of 4.8 ± 1.46 g/day (range 3.0 to 7.5). Despite the 8 hour dosing interval, the variation between maximal and minimal plasma procainamide and N-acetylprocainamide concentrations under steady state conditions was very small. Mean maximal procainamide and N-acetylprocainamide plasma concentrations were 10.4 ± 6.02 and 12.0 ± 7.40 μg/ml, respectively. The respective mean minimal concentrations were 6.8 ± 4.50 and 8.7 ± 5.99 μg/ml. In nine patients (27 percent) treatment with sustained release procainamide resulted in conversion of the antinuclear antibody test from negative to positive. Adverse drug effects occurred in 17 (52 percent) of the subjects. In general, adverse effects were minor and abated within 24 hours after administration of the drug was stopped. One patient had the procainamide-induced systemic lupus erythematosus-like syndrome.
• Gierke, K. D., Graves, P. E., Perrier, D., Marcus, F. I., Mayersohn, M., & Goldman, S. (1980). Metabolism and rate of elimination of digoxigenin bisdigitoxoside in dogs before and during chronic azotemia. Journal of Pharmacology and Experimental Therapeutics, 212(3), 448-451.
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  PMID: 7359346;Abstract: The purpose of this study was to evaluate the metabolism and rate of elimination of digoxigenin bisdigitoxoside (bis) before and during chronic azotemia in dogs. Bis was eliminated primarily by nonrenal mechanisms. The half-life of bis was 18.5 hr, compared to 31.6 hr for digoxin, and was not significantly increased in azotemic dogs. The oral bioavailability of bis in azotemic dogs relative to an intravenous dose was approximately 46%.
• Walson, P. D., Mimaki, T., & Mayersohn, M. (1980). Serum and salivary phenobarbital levels after once daily dosing of epileptic children. Clinical Research, 28(1), 91A.
• Walson, P. D., Mimaki, T., Curless, R., Mayersohn, M., & Perrier, D. (1980). Once daily doses of phenobarbital in children. The Journal of Pediatrics, 97(2), 303-305.
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  PMID: 7400905;
• Alberts, D. S., Chen, H. -., Mayersohn, M., Perrier, D., Moon, T. E., & Gross, J. F. (1979). Bleomycin pharmacokinetics in man - II. Intracavitary administration. Cancer Chemotherapy and Pharmacology, 2(2), 127-132.
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  PMID: 93985;Abstract: Disposition of bleomycin was studied in plasma and urine (14 patients) and ascites fluid (2 patients) after intraperitoneal (IP) and intrapleural (IPl) administration, by radioimmunoassay. Peak plasma bleomycin concentrations after 60 U/m2 in 12 patients ranged between 0.4 and 5.0 mU/ml. For those patients with creatinine clearances greater than 50 ml/min the composite terminal phase bleomycin plasma half-lives (±SD) for three 'IPl' and six 'IP' patients were 3.4±0.3 and 5.3±0.4 h, respectively. The composite IP plasma half-life was significantly longer than the IPl hal-life (P
• Hager, W. D., Fenster, P. E., & Mayersohn, M. (1979). Digoxin-quinidine interaction: Pharmocokinetic evaluation. Clinical Research, 27(2), 233A.
• Hager, W. D., Fenster, P., Mayersohn, M., Perrier, D., Graves, P., Marcus, F. I., & Goldman, S. (1979). Digoxin-quinidine interaction. Pharmacokinetic evaluation. New England Journal of Medicine, 300(22), 1238-1241.
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  PMID: 431681;Abstract: Several recent reports have shown that plasma concentrations of digoxin increase when quinidine is administered along with digoxin; the present study was designed to explore the pharmacokinetics of this digoxin-quinidine interaction in six subjects. The elimination half-life of digoxin, although variable, did not change appreciably (42 vs. 44 hours) when quinidine was administered. Other pharmacokinetic values were substantially reduced in the presence of quinidine: total body clearance (from 3.08 to 1.96 ml per minute per kilogram), renal clearance (from 1.64 to 1.09 ml per minute per kilogram) and volume of distribution (from 10.87 to 7.35 liters per kilogram). The results may be explained by the displacement of digoxin from binding sites in tissue by quinidine, causing a rise in the plasma concentration of digoxin. The reduction in renal clearance of digoxin may result also from inhibition of renal secretion of digoxin by quinidine.
• Mayersohn, M., Perrier, D., Fenster, P., & Marcus, F. I. (1979). Steady-state plasma concentrations of quinidine and propranolol. American Heart Journal, 97(5), 678-.
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  PMID: 433743;
• Alberts, D. S., Chen, H. -., Liu, R., Himmelstein, K. J., Mayersohn, M., Perrier, D., Gross, J., Moon, T., Broughton, A., & Salmon, S. E. (1978). Bleomycin pharmacokinetics in man - I. Intravenous administration. Cancer Chemotherapy and Pharmacology, 1(3), 177-181.
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  PMID: 86392;Abstract: Bleomycin plasma decay kinetics and urinary excretion were studied in nine patients after IV bolus injections of 13.7 to 19.9 U/M2. Radio-immunoassay was used to measure bleomycin in plasma and urine samples. The resulting plasma concentration versus time data for each patient and the combined data obtained from all patients were fitted to a multiexponential equation using a nonlinear regression computer program. Pharmacokinetic parameters derived from the mean of all individual patient parameters and the composite of all plasma decay data were similar. Bleomycin initial and terminal plasma half-lives and volume of distribution for all plasma decay data from eight patients with normal serum creatinies were 24.4±4.0 min, 237.5±8.5 min, and 17.3±1.5 L/M2, respectively. Mean 24-h urinary excretion accounted for 44.8±12.6% of the dose in seven patients who had normal serum creatinine values and complete urine collections. The total body clearance and renal clearance in these seven patients averaged 50.5±4.1 ml/min/M2 and 23.0±1.9 ml/min/M2, respectively. One patient with a serum creatinine of 1.5 mg% (normal 0.7 to 1.3 mg%) who was given 15.6 U/M2 had a terminal plasma halflife of 624 min, a volume of distribution of 36.3 L/M2, and 24-h urinary excretion of 11.6% of the dose. We conclude that bleomycin after intravenous bolus injection has a relatively short terminal phase plasma halflife and relatively large urinary elimination. © 1978 Springer-Verlag.
• Cobby, J., Mayersohn, M., & Selliah, S. (1978). Disposition kinetics in dogs of diethyldithiocarbamate, a metabolite of disulfiram. Journal of Pharmacokinetics and Biopharmaceutics, 6(5), 369-387.
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  PMID: 215740;Abstract: Following the intravenous infusion of sodium diethyldithiocarbamate to dogs, the disposition kinetics of diethyldithiocarbamate (DDC), a metabolite of disulfiram, were assessed. Approximately 27% of the administered dose was S-methylated, this process exhibiting a mean first-order rate constant of 0. 0569 min-1 (t1/2=12.2 min), while the remainder was eliminated by other routes having a rate constant of 0.148 min-1 (t1/2=4.68 min). The methyl diethyldithiocarbamate (MeDDC) formed from DDC showed an elimination rate constant of 0.0141 min-1 (t1/2=49.2 min). These observations are discussed in the light of previous investigations where the presence of MeDDC has rarely been sought or reported. A few comparisons with prior studies, in which DDC or disulfiram was administered, are made by retrospective kinetic evaluation of published data. The results are discussed in relation to the duration of action of disulfiram in man. © 1978 Plenum Publishing Corporation.
• Dickerson, J., Perrier, D., Mayersohn, M., & Bressler, R. (1978). Dose tolerance and pharmacokinetic studies of L (+) pseudoephedrine capsules in man. European Journal of Clinical Pharmacology, 14(4), 253-259.
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  PMID: 729619;Abstract: Dose tolerance and pharmacokinetic studies of pseudoephedrine sustained action capsules were performed in thirty-three adult male subjects who received either 120 mg or 150 mg capsules every twelve hours for seven consecutive days in a double-blind parallel design study. Although only one subject in the 150 mg group was discontinued prematurely from this study, a large number of side effects typical of CNS stimulation were seen. A placebo effect might account for a portion of these complaints, however symtoms evaluated as being due to drug were significantly more severe and persistent in the 150 mg group. Pulse rates showed a persistent and significant increase while systolic and diastolic blood pressure fell from the baseline values in both groups. A pharmacokinetic analysis of the pseudoephedrine plasma concentration-time data provided estimates of half-life and the volume of distribution/availability ratio. The values obtained were in good agreement with values reported by others. Half-life was not influenced by urine pH probably as a result of the narrow range of urine pHs observed in the subjects. Calculations of relative bioavailability suggest that the 120 mg capsule formulation has a 30% greater bioavailability compared to the 150 mg capsule. © 1978 Springer-Verlag.
• Gierke, K. D., Perrier, D., Mayersohn, M., & Marcus, F. I. (1978). Digoxin disposition kinetics in dogs before and during azotemia. Journal of Pharmacology and Experimental Therapeutics, 205(2), 459-464.
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  PMID: 641840;Abstract: The purpose of this study was to evaluate the disposition kinetics of digoxin after the administration of a single intravenous dose to the same dogs before and during azotemia. The digoxin plasma concentration-time data were fitted to a multicompartment model using nonlinear regression analysis. During azotemia, the biological half-life of digoxin was prolonged in six of seven dogs, while digoxin renal clearance, body clearance and apparent volume of distribution were significantly decreased. There was a corresponding increase in the apparent volume of the 'central' compartment of digoxin. Approximately 45% of a digoxin dose was excreted by the kidney in these animals indicating a substantial nonrenal component to digoxin elimination in the dog. This nonrenal elimination did not change during azotemia, despite a decrease in renal clearance by 61%.
• Mayersohn, M., & Perrier, D. (1978). Kinetics of pharmacologic response to cocaine. Research Communications in Chemical Pathology and Pharmacology, 22(3), 465-474.
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  PMID: 734226;Abstract: Cocaine plasma concentration-response-time data obtained from the literature were analyzed by pharmacokinetic methods. The plasma concentration-time data yield an elimination half-life of approximately 1 hour and the data suggest that only about 20% of an oral dose of cocaine is absorbed intact into the systemic circulation. Response, as assessed by means of a relative 'high' rating scale, declined linearly with time as predicted by theory. The rate of decline of response was found to be 0.0221 'high'/min. The rate of decline of response is a function of the apparent first-order elimination rate constant (K) of the drug and the slope of the response-log plasma concentration curve (m). A value for m of 4.2 'high' was calculated from the response-time data which agreed well with a value of 3.9 'high' for m determined from the slope of the response-log plasma concentration curve.
• Okada, R. D., Hager, W. D., Graves, P. E., Mayersohn, M., Perrier, D. G., & Marcus, F. I. (1978). Relationship between plasma concentration and dose of digoxin in patients with and without renal impairment. Circulation, 58(6), 1196-1203.
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  PMID: 709776;Abstract: The purpose of this study was to determine if there is a linear relationship between oral doses of digoxin and various measurements of steady-state digoxin plasma concentration and urinary excretion in patients with a wide range of renal function. Ten patients (mean age 58 years) with creatinine clearances < 50 ml/min/1.73 m 2 BSA (mean creatinine clearance 80 ml/min/1.73 m 2 BSA) and nine patients (mean age 61 years) with creatinine clearances
• Yung, S., Mayersohn, M., & Robinson, J. B. (1978). Ascorbic acid elimination in humans after intravenous administration. Journal of Pharmaceutical Sciences, 67(10), 1491-1492.
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  PMID: 702316;
• Cobby, J., Mayersohn, M., & Selliah, S. (1977). Methyl diethyldithiocarbamate, a metabolite of disulfiram in man. Life Sciences, 21(7), 937-941.
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  PMID: 200811;Abstract: Following the oral administration of disulfiram to alcoholic patient volunteers, methyl diethyldithiocarbamate (MeDDC) was noted in blood withdrawn between one and two hours after dosing. This is consistent with previous reports of MeDDC in mice and dogs. It is suggested that MeDDC is an intermediate in the formation of urinary sulfate. © 1977.
• Cobby, J., Mayersohn, M., & Selliah, S. (1977). The rapid reduction of disulfiram in blood and plasma. Journal of Pharmacology and Experimental Therapeutics, 202(3), 724-731).
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  PMID: 197231;Abstract: A gas chromatographic assay procedure was developed to quantitate the reduction product of disulfiram, diethyldithiocarbamate (DDC), in blood and plasma. The procedure involved the in situ methylation of DDC prior to the extraction and chromatography of the methyl ester. The minimal sensitivity achieved was 0.2 μg/ml from 1 ml of blood or plasma. The coefficient of variation about any concentration was 10.5%. Calibration curves having a reproducible nonlinear form were prepared up to 9 μg/ml. The assay procedure was used to evaluate the stability of disulfiram and DDC in blood. Disulfiram was rapidly and quantitatively reduced to DDC within 4 minutes. The DDC thus formed decomposed in human and dog blood with half lives of 70 and 100 minutes respectively. The implications of these findings are discussed with respect to the chemical form of disulfiram responsible for the ethanol-sensitizing effect.
• Kapur, B. M., Danglay, B., & Mayersohn, M. (1977). 'In situ' TLC quantitation of amitriptyline and nortriptyline using HP TLC and transferable calibration factor. Clinical Chemistry, 23(6), No.063.
• Mayersohn, M., Chow, M. S., Kostenbauder, H. B., & Rowland, M. (1977). Aspirin.. Journal of the American Pharmaceutical Association, 17(2), 107-112.
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  PMID: 845363;
• Mayersohn, M., Perrier, D., & Picchioni, A. L. (1977). Evaluation of a charcoal-sorbitol mixture as an antidote for oral aspirin overdose. Clinical Toxicology, 11(5), 561-567.
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  PMID: 608318;
• Perrier, D., Mayersohn, M., & Marcus, F. I. (1977). Clinical pharmacokinetics of digitoxin. Clinical Pharmacokinetics, 2(4), 292-311.
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  PMID: 902449;Abstract: The disposition kinetics of digitoxin have not been as thoroughly examined as those of digoxin. Digitoxin appears to be rapidly and completely absorbed after oral or intramuscular administration although there have been no estimates of absolute bioavailability. There is only one study that has examined the relative bioavailability of two commercial digitoxin tablets (USA) and no differences were found other than in rates of absorption. The near identical responses produced by equal oral and intravenous doses of digitoxin support the suggestion of completeness of absorption. The digitoxin plasma concentration-time curve seems to be adequately described by a two compartment open model, although such data have not been rigorously analyzed. Distribution is complete within 4 to 6 hr and response is not associated with plasma concentrations during the distributive phase, suggesting that the site of action resides in a tissue compartment of a multi-compartment pharmacokinetic model. Digitoxin is strongly bound (>90%) to plasma protein (albumin) with an association constant of 9.62 x 104 litre/mole. The volume of distribution of digitoxin is approximately 0.6 L/kg, although estimates vary considerably. This volume is much smaller than digoxin, consistent with the great plasma protein binding of digitoxin. As with the estimation of the other pharmacokinetic parameters of digitoxin, estimates of elimination vary greatly, primarily as a result of differences in assay methods. Digitoxin is eliminated by hepatic metabolism and as unchanged drug in the urine and feces. Metabolism is considered to be the major route of elimination, accounting for about 70% of a dose. While most reports indicate that only 30% of a digitoxin dose is eliminated intact (in urine and feces) this value may be as high as 48%. Digitoxin elimination appears to be independent of dose and route of administration, although there is substantial inter-patient variation in elimination half-life. Half-lives range from 2.4 to 16.4 days with a mean value of approximately 7.6 days. The shortest mean half-life (4.8 days) was observed with the most specific assay and the longest mean half-life (9.8 days) with the least specific method. Renal insufficiency has been reported to result in either decreased or increased digitoxin elimination. While elimination may be expected to increase if plasma protein binding is reduced, there are conflicting reports on the influence of renal insufficiency on digitoxin binding. Part of this conflict may be resolved with the observation that patients undergoing hemodialysis and who receive heparin have a greater fraction of free digitoxin in plasma soon after heparin administration. It appears that plasma free fatty acid concentrations increase in response to heparin which in turn competes with digitoxin for albumin binding sites. Digitoxin half-life is reported to be shortened and volume of distribution increased in nephrotic patients. The influence of hepatic impairment on digitoxin elimination has not been thoroughly examined and there is only one report suggesting reduced elimination in this situation. Cholestyramine has been shown to reduce digitoxin half-life by interfering with the enterohepatic recycling of the drug. There have been no reports to indicate that other drugs may displace digitoxin from plasma protein binding sites. Concurrent administration of phenylbutazone, phenobarbitone, and phenytoin decreases digitoxin plasma concentrations; presumably by inducing digitoxin metabolism. Phenobarbitone, rifampicin and spironolactone have been reported to decrease digitoxin half-life. Numerous studies have attempted to better define the therapeutic plasma concentration range of digitoxin. Plasma concentrations greater than 35 to 40 ng/ml are generally considered to be associated with potential toxicity while concentrations from 15 to 25 ng/ml are considered to be within the therapeutic range. As with digitoxin there is considerable variation and overlap in plasma concentrations associated with toxicity and therapeutic response.
• Mahon, W. A., Mayersohn, M., & Inaba, T. (1976). Disposition kinetics of two oral forms of quinidine. Clinical Pharmacology and Therapeutics, 19(5 PART 1), 566-575.
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  PMID: 1277713;Abstract: There are relatively few studies on the disposition properties of quinidine. We have studied in 10 normal subjects conventional quinidine sulfate and a slow-release quinidine bisulfate. Single and repetitive doses were given; blood and urine concentrations were measured by the method of Cramer and Isaakson.5 After a single dose of two tablets of quinidine sulfate (400 mg), the average peak concentration was 2.13 ± 0.22 μg/ml (±SEM); following two tablets of the slow-release form, the average peak concentration was 1.17 ± 0.12 μg/ml T-max was approximately 2 hr with quinidine sulfate and 4 hr with quinidine bisulfate. One fourth of both forms of the drug was recovered in the urine. Total body clearance was 0.36 Llkg ·hr and renal clearance was 117 ± 22 ml/min for both. With multiple dosing the serum quinidine concentration was higher than these predicted from the results of the single-dose study. Based on the mean estimates of quinidine half-life of 6 hr, a rapid method for achieving steady-state levels of quinidine would be to give an initial dose twice that of the maintenance dose. With the slow-release product if an equivalent dose was given every 12 hr, the mean steady-state quinidine serum concentration would be approximately the same. © 1976.
• Mahon, W. A., Mayersohn, M., & Inaba, I. (1975). Pharmacokinetics and bioavailability of two oral forms of quinidine. Clinical Research, 23(5), 609a.
• Cobby, J., Mayersohn, M., & Farlinger, B. (1974). The dissolution of drug particles under sink conditions. Canadian Journal of Pharmaceutical Sciences, 9(4), 91-96.
• Cobby, J., Mayersohn, M., & Walker, G. C. (1974). Influence of shape factors on kinetics of drug release from matrix tablets. I: Theoretical. J.PHARM.SCI., 63(5), 725-732.
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  PMID: 4829995;
• Cobby, J., Mayersohn, M., & Walker, G. C. (1974). Influence of shape factors on kinetics of drug release from matrix tablets. II: Experimental. J.PHARM.SCI., 63(5), 732-737.
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  PMID: 4829996;
• Mayersohn, M., & Endrenyi, L. (1973). Relative bioavailability of commercial ampicillin formulations in man. Canadian Medical Association Journal, 109(10), 989-993.
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  PMID: 4758871;PMCID: PMC1947011;Abstract: The relative bioavailability of three commercial ampicillin products was examined in 12 human subjects using a crossover experimental design. Based upon the areas under the ampicillin plasma concentration time curves after the oral administration of 250 mg. ampicillin and using an analysis of variance technique, no statistically significant differences were found between the products examined. These findings are in contrast to those of a recent report and appear to be explained by formulation differences. These relatively minor differences in formulation reflect the importance of formulation variables in providing efficient drug therapy. The intrasubject variation associated with several of these products is quite marked and is consistent with the incomplete and erratic absorption of this antibiotic in man.
• Mayersohn, M., & Suryasaputra, K. (1973). Transport cell for examining solute transfer across biological membranes.. Journal of Pharmaceutical Sciences, 62(4), 681-683.
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  PMID: 4698996;
• Mayersohn, M. (1972). Ascorbic acid absorption in man - pharmacokinetic implications. European Journal of Pharmacology, 19(1), 140-142.
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  PMID: 5048660;Abstract: Several early literature reports have suggested the possible existence of a non-passive, saturable process for ascorbic acid absorption in man. The recent work of several investigators confirms the existence of such a mechanism. Based upon an analysis of the data provided by these investigators values of Vmax and Km have been calculated using the equations of saturable absorption kinetics. A method of oral dosing is suggested which should maximize the total amount of vitamin absorbed. © 1972.
• Mayersohn, M., & Gibaldi, M. (1971). Drug transport. 3. Influence of various sugars on passive transfer of several drugs across the everted rat intestine.. Journal of Pharmaceutical Sciences, 60(2), 225-230.
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  PMID: 5572444;
• Mayersohn, M., & Gibaldi, M. (1971). Drug transport. IV. Influence of hypotonic and hypertonic solutions on passive drug transfer across the everted rat intestine.. Journal of Pharmaceutical Sciences, 60(2), 326-327.
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  PMID: 5572470;
• Mayersohn, M., Gibaldi, M., & Grundhofer, B. (1971). Drug transport. V. Mechanism of potassium-ion inhibition of passive transfer of solutes across everted rat intestine.. Journal of Pharmaceutical Sciences, 60(12), 1813-1817.
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  PMID: 5157995;
• Mayersohn, M., & Gibaldi, M. (1970). Drug transport. II. The effect of various cations on the passive transfer of drugs across the everted rat intestine. BBA - Biomembranes, 196(2), 296-304.
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  PMID: 5414307;Abstract: 1. 1. It has been shown in a previous report that replacement of Na+ by K+ in a Krebs bicarbonate buffer significantly reduced the passive transfer of several water-soluble drugs across the everted rat intestine. As an extension of that study the influence of other cations (vis. NH4+, Li+, Tris+, and guanidine+) and the dependence of the drug-transfer rate on K+ concentration, have been examined. 2. 2. It is shown that ouabain (1 mM) in the Na+ control buffer has no effect on the transfer process of riboflavin, salicylate and sulfanilamide. NH4+ and guanidine+, as well as K+ significantly reduced the transfer of riboflavin while Tris+ had no effect; NH4+ and K+ decreased salicylate transfer and Li+ and K+ inhibited sulfanilamide transfer. Increasing concentrations of K+ caused a progressive decrease in riboflavin transfer. 3. 3. The effect of these various cations on the tissue fluid uptake was examined. Good agreement with previously published results has been obtained. The fluid uptake by rat intestinal segments is strongly influenced by the major cation in the buffer solution and decreases in the following order K+ > NH4+ > Li+ > Na+ control > guanidine+ > Tris+. 4. 4. The inhibition of riboflavin transfer by various cations appears to correlate well with the degree of tissue fluid uptake by intestinal tissue. © 1970.
• Mayersohn, M., & Gibaldi, M. (1969). Drug Transport. I. Effect of potassium ion on the in vitro transfer of several drugs across the rat intestine: preliminary observations.. Journal of Pharmaceutical Sciences, 58(11), 1429-1430.
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  PMID: 5349771;
• Mayersohn, M., Feldman, S., & Gibaldi, M. (1969). Bile salt enhancement of riboflavin and flavin mononucleotide absorption in man.. Journal of Nutrition, 98(3), 288-296.
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  PMID: 4894307;
• Goldberg, A. H., Gibaldi, M., Kanig, J. L., & Mayersohn, M. (1966). Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures. IV. Chloramphenicol--urea system.. Journal of Pharmaceutical Sciences, 55(6), 581-583.
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  PMID: 5924122;
• Mayersohn, M., & Gibaldi, M. (1966). New method of solid-state dispersion for increasing dissolution rates.. Journal of Pharmaceutical Sciences, 55(11), 1323-1324.
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  PMID: 5969799;