Cytochrome P450 Turnover: Regulation of Synthesis and Degradation, Methods for Determining Rates, and Implications for the Prediction of Drug Interactions
In vivo enzyme levels are governed by the rates of de novo enzyme synthesis and degradation. A current lack of consensus on values of the in vivo turnover half-lives of human cytochrome P450 (CYP) enzymes places a significant limitation on the accurate prediction of changes in drug concentration-time profiles associated with interactions involving enzyme induction and mechanism (time)-based inhibition (MBI). In the case of MBI, the full extent of inhibition is also sensitive to values of enzyme turnover half-life. We review current understanding of CYP regulation, discuss the pros and cons of various in vitro and in vivo approaches used to estimate the turnover of specific CYPs and, by simulation, consider the impact of variability in estimates of CYP turnover on the prediction of enzyme induction and MBI in vivo. In the absence of consensus on values for the in vivo turnover half-lives of key CYPs, a sensitivity analysis of predictions of the pharmacokinetic effects of enzyme induction and MBI to these values should be an integral part of the modelling exercise, and the selective use of values should be avoided.
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Document Type: Research Article
Publication date: 2008-06-01
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- Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:
In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.