The use of hepatocytes in evaluating time-dependent inactivation of P450 in vivo.
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.
Zhao
Ping
P
Sonus Pharmaceuticals, Bothell, WA 98021, USA. pingzhao1990@yahoo.com
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
D004791:Enzyme Inhibitors; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System