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.