PT - JOURNAL ARTICLE AU - Yoichi Naritomi AU - Shigeyuki Terashita AU - Sumihisa Kimura AU - Akira Suzuki AU - Akira Kagayama AU - Yuichi Sugiyama TI - Prediction of Human Hepatic Clearance from in Vivo Animal Experiments and in Vitro Metabolic Studies with Liver Microsomes from Animals and Humans DP - 2001 Oct 01 TA - Drug Metabolism and Disposition PG - 1316--1324 VI - 29 IP - 10 4099 - http://dmd.aspetjournals.org/content/29/10/1316.short 4100 - http://dmd.aspetjournals.org/content/29/10/1316.full SO - Drug Metab Dispos2001 Oct 01; 29 AB - 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 (CLint) values for each compound were measured and calculated in rats and/or dogs and humans. CLint,in vitro was determined from a substrate disappearance rate at 1 μM in hepatic microsomes, which was a useful method. CLint,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 (CLint,in vivo/CLint,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 CLint,in vitro values were compared with the actual CLint,in vivo, correlation was not necessarily good. By contrast, using human CLint,in vitrocorrected with the rat and/or dog scaling factors yielded better predictions of CLint,in vivo that were mostly within 2-fold of the actual values. Furthermore, successful predictions of human CLoral and hepatic extraction ratio (EH) were obtained by use of the human CLint,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. The American Society for Pharmacology and Experimental Therapeutics