PREDICTION OF IN VIVO HUMAN HEPATIC CLEARANCE IN DRUG DISCOVERY

Abstract

We have investigated a quantitative prediction of in vivo human hepatic clearance from in vitro experiments. In vivo intrinsic clearance (CLint, in vivo) were compared with in vitro intrinsic clearance (CLint, in vitro) from in vitro metabolism data obtained by using liver microsomes focusing on P450 metabolism in rats, dogs and humans. The scaling factor (CLint, in vivo/CLint, in vitro) were different among the model compounds, while most of the animal scaling factors were within 2-fold of the values in humans. When human CLint, in vitro values were compared with the actual CLint, in vivo, correlations were not necessarily good. By contrast, using human CLint, in vitro corrected with the animal scaling factor yielded better predictions of CLint, in vivo that were mostly within 2-fold of actual values. Further, CLint, in vivo were compared with CLint, in vitro from in vitro metabolismd ata obtained by using rat fresh and human cryopreserved hepatocytes. Human CLint, in vitro corrected with the rat scaling factor yielded good predictions of CLint, in vivo that were mostly less than several-fold of actual values. This method thus provides a more reliable prediction of human hepatic clearance and will be useful in drug discovery.