Prediction of interindividual variation in drug plasma levels in vivo from individual enzyme kinetic data and physiologically based pharmacokinetic modeling
article
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
Topics
Cytochrome P450Interindividual variationMetabolismPhysiologically based pharmacokinetic modelingAgomelatineBufuralolChlorzoxazoneCoumarinCytochrome P450DiclofenacEthoxyresorufinMephenytoinTestosteroneClinical trialControlled clinical trialControlled studyDrug blood levelEnzyme kineticsFood drug interactionGenetic polymorphismHumanHuman cellHuman experimentHuman tissueLiver microsomeMaleModelNormal humanPhase 1 clinical trialPhenotypePriority journalAcetamidesCell LineCytochrome P-450 Enzyme SystemHumansHypnotics and SedativesIsoenzymesKineticsMicrosomes, LiverModels, BiologicalPharmaceutical PreparationsPharmacokineticsRecombinant ProteinsTransfection
TNO Identifier
72127
ISSN
09280987
Source
European Journal of Pharmaceutical Sciences, 12(2), pp. 117-124.
Pages
117-124
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