Abstract

We investigated the quantitative prediction of human hepatic metabolic clearance from in vitro experiments focusing on cytochrome P450 metabolism with eight model compounds, FK1052, FK480, zolpidem, omeprazole, nicardipine, nilvadipine, diazepam, and diltiazem. For the compounds, in vivo human hepatic extraction ratios ranged widely from 0.03 to 0.87. In vitro and in vivo hepatic intrinsic clearance (CL_int) values for each compound were measured and calculated in rats and/or dogs and humans. CL_{int,in vitro} was determined from a substrate disappearance rate at 1 μM in hepatic microsomes, which was a useful method. CL_{int,in vivo} was calculated from in vivo pharmacokinetic data using three frequent mathematical models (the well stirred, parallel-tube, and dispersion models). The human scaling factor values (CL_{int,in vivo}/CL_{int,in vitro}) showed marked difference among the model compounds (0.3–26.6-fold). On the other hand, most of the animal scaling factors were within 2-fold of the values in humans, suggesting that scaling factor values were similar in the different animal species. When human CL_{int,in vitro} values were compared with the actual CL_{int,in vivo}, correlation was not necessarily good. By contrast, using human CL_{int,in vitro}corrected with the rat and/or dog scaling factors yielded better predictions of CL_{int,in vivo} that were mostly within 2-fold of the actual values. Furthermore, successful predictions of human CL_oral and hepatic extraction ratio (E_H) were obtained by use of the human CL_{int,in vitro} corrected with animal scaling factors. The new variant method is a simple one, incorporating additional information from animal studies and providing a more reliable prediction of human hepatic clearance.