QUANTITATIVE PREDICTION OF IN VIVO METABOLIC CLEARANCE AND DRUG-DRUG INTERACTIONS IN HUMANS BASED ON IN VTIRO STUDIES

The in vitro intrinsic clearances (CLint, in vitro) of P450-mediated reactions obtained by using human liver microsomes were compared with the in vivo intrinsic clearances (CLint, in vivo) which were calculated from pharmacokinetic data in literature. Although CLint, in vitro and CLint, in vivo agreed well with each other for most of the drugs investigated, more than 10-fold differences were observed for some drugs, indicating the possible involvement of the first-pass metabolism in the gut and/or interindividual variability in the hepatic metabolism. The AUCoral and bioavailability of YM796, a compound being developed for the treatment of dementia, were well predicted from in vitro metabolic studies taking the non-linear first-pass metabolism into consideration. Furthermore, we have tried to predict in vivo drug-drug interactions from in vitro data on drug metabolism obtained from the literature. Assuming the same unbound concentration of the inhibitor in the liver and in plasma, the degree of increase in the AUC caused by the metabolic inhibition was underestimated for some of the drug combinations. The transport study using isolated rat hepatocytes indicated that the contribution of the active transport of the inhibitors such as quinidine, erythromycin etc. into the hepatocytes is not so large. The drug-drug interactions involving the gastrointestinal absorption process may have to be considered for the more precise prediction.