Cytochrome P450 Turnover: Regulation of Synthesis and Degradation, Methods for Determining Rates, and Implications for the Prediction of Drug Interactions

Jiansong      Yang; Mingxiang      Liao; Magang      Shou; Masoud      Jamei; Karen   Rowland   Yeo; Geoffrey   T.   Tucker; Amin      Rostami-Hodjegan

Abstract

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.

Keywords: Cytochrome P450, drug interactions, enzyme degradation, enzyme regulation, enzyme turnover, induction, mechanism-based inhibition

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