The use of hepatocytes in evaluating time-dependent inactivation of P450 in vivo

Abstract

Background: Time-dependent inactivation (TDI) of P450 is an important mechanism of drug interactions. The quantitative in vitro–in vivo correlation of TDI using systems such as human liver microsomes requires a comprehensive understanding of in vitro kinetics, pharmacokinetics, inhibition mechanisms, and homeostasis of the enzyme being inactivated. Objective: To evaluate the use of hepatocytes in predicting TDI. Methods: The theoretical basis of in vitro–in vivo correlation of TDI and the progress in using microsomes and hepatocytes to predict TDI in vivo are reviewed. Results/conclusion: Factors that may impact prediction accuracy, such as nonspecific binding, metabolism of inactivator, active transport, and sequential inhibitory metabolites, can be assessed by performing ‘in vitro–in vitro’ correlation between microsomes and hepatocytes. Together with microsomal data and the aid of computer modeling and simulation, hepatocytes provide a powerful tool to optimize the integrated approaches aimed at quantitatively predicting TDI in vivo.

Keywords::

• hepatocytes
• in vitro–in vivo correlation
• time-dependent inactivation

Notes