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

Expert Opin Drug Metab Toxicol. 2008 Feb;4(2):151-64. doi: 10.1517/17425255.4.2.151.


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.

Publication types

  • Review

MeSH terms

  • Cytochrome P-450 Enzyme System / drug effects*
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Interactions*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Forecasting
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Humans
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Models, Biological
  • Pharmaceutical Preparations / metabolism
  • Time Factors


  • Enzyme Inhibitors
  • Pharmaceutical Preparations
  • Cytochrome P-450 Enzyme System