title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Sonus Pharmaceuticals, Bothell, WA 98021, USA. pingzhao1990@yahoo.com
authors.forename: Ping
authors.initials: P
authors.lastname: Zhao
mesh_terms: D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005544:Forecasting; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System