Abstract

The clearance route and the absolute values for hepatic and renal clearance of drugs are important criteria for the selection of drug candidates. Based on pharmacokinetic theory, by assuming that uptake is the rate-determining process for the biliary excretion of drugs, organ intrinsic clearance should be simply estimated by the intrinsic uptake. In this study, to investigate whether organ clearance can be predicted from the in vitro uptake activity, we performed uptake experiments using isolated hepatocytes and kidney slices, integration plot analyses, and in vivo pharmacokinetic studies using 12 barely metabolized drugs in rats. The in vivo hepatic and renal clearance could be approximated by uptake clearance estimated from integration plot analyses, except for the renal clearance of some drugs that was relatively small. The comparison of intrinsic uptake clearance from in vitro experiments and integration plot studies revealed that in vivo hepatic uptake was well explained by uptake into isolated hepatocytes, whereas in kidney, in vivo uptake clearance was 10 to 100 times that in kidney slices and a scaling factor is required for its prediction from in vitro experiments. The organ clearance and the fraction excreted into urine could be predicted from in vitro studies except for drugs whose renal clearance was relatively small. This study suggests that the uptake process is the determining factor for organ clearance of minimally metabolized drugs, and uptake assays using isolated hepatocytes and kidney slices are useful for evaluating the uptake clearance.