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Prediction of interindividual variation in drug plasma levels in vivo from individual enzyme kinetic data and physiologically based pharmacokinetic modeling

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Author: Bogaards, J.J.P. · Hissink, E.M. · Briggs, M. · Weaver, R. · Jochemsen, R. · Jackson, P. · Bertrand, M. · Bladeren, P. van
Type:article
Date:2000
Institution: Centraal Instituut voor Voedingsonderzoek TNO
Source:European Journal of Pharmaceutical Sciences, 2, 12, 117-124
Identifier: 72127
doi: doi:10.1016/S0928-0987(00)00146-9
Keywords: Nutrition · Cytochrome P450 · Interindividual variation · Metabolism · Physiologically based pharmacokinetic modeling · Agomelatine · Bufuralol · Chlorzoxazone · Coumarin · Cytochrome P450 · Diclofenac · Ethoxyresorufin · Mephenytoin · Testosterone · Clinical trial · Controlled clinical trial · Controlled study · Drug blood level · Enzyme kinetics · Food drug interaction · Genetic polymorphism · Human · Human cell · Human experiment · Human tissue · Liver microsome · Male · Model · Normal human · Phase 1 clinical trial · Phenotype · Priority journal · Acetamides · Cell Line · Cytochrome P-450 Enzyme System · Humans · Hypnotics and Sedatives · Isoenzymes · Kinetics · Microsomes, Liver · Models, Biological · Pharmaceutical Preparations · Pharmacokinetics · Recombinant Proteins · Transfection

Abstract

A strategy is presented to predict interindividual variation in drug plasma levels in vivo by the use of physiologically based pharmacokinetic modeling and human in vitro metabolic parameters, obtained through the combined use of microsomes containing single cytochrome P450 enzymes and a human liver microsome bank. The strategy, applied to the pharmaceutical compound (N-[2-(7-methoxy-1-naphtyl)-ethyl]acetamide), consists of the following steps: (1) estimation of enzyme kinetic parameters K(m) and V(max) for the key cytochrome P450 enzymes using microsomes containing individual P450 enzymes; (2) scaling-up of the V(max) values for each individual cytochrome P450 involved using the ratio between marker substrate activities obtained from the same microsomes containing single P450 enzymes and a human liver microsome bank; (3) incorporation into a physiologically based pharmacokinetic model. For validation, predicted blood plasma levels and pharmacokinetic parameters were compared to those found in human volunteers: both the absolute plasma levels as well as the range in plasma levels were well predicted. Therefore, the presented strategy appears to be promising with respect to the integration of interindividual differences in metabolism and prediction of the possible impact on plasma and tissue concentrations of drugs in humans. Copyright (C) 2000 Elsevier Science B.V. Chemicals/CAS: Acetamides; Cytochrome P-450 Enzyme System, 9035-51-2; Hypnotics and Sedatives; Isoenzymes; Pharmaceutical