PREDICTION OF IN-VIVO DRUG-METABOLISM IN THE HUMAN LIVER FROM IN-VITRO METABOLISM DATA

As a new approach to predicting in vivo drug metabolism in humans, sca ling of in vivo metabolic clearance from in vitro data obtained using human liver microsomes or hepatocytes is described in this review, bas ed on the large number of literature data. Successful predictions were obtained for verapamil, loxtidine (lavoltidine), diazepam, lidocaine, phenacetin and some other compounds where CL(int,in vitro), is compar able with CL(int,in vivo). On the other hand, for some metabolic react ions, differences in CL(int,in vitro) and CL(int,in vivo) greater than 5-fold were observed. The following factors are considered to be the cause of the differences: (1) metabolism in tissues other than liver, (2) incorrect assumption of rapid equilibrium of drugs between blood a nd hepatocytes, (3) presence of active transport through the sinusoida l membrane, and (4) interindividual variability. Furthermore, the poss ibility of predicting in vivo drug metabolic clearance from results ob tained using a recombinant system of human P450 isozyme was described for a model compound, YM796, where the predicted metabolic clearances obtained from the recombinant system, taking account of the content of the P450 isozyme CYP3A4 in the human microsomes, were comparable with the observed clearances using human liver microsomes containing diffe rent amounts of CYP3A4. Even in the case where the first-pass metaboli sm exhibits nonlinearity, it appears to be possible to predict in vivo metabolic clearance from in vitro metabolic data. (C) 1997 Elsevier S cience Inc.