Intrinsic clearances (CLint-HLM-total) for the metabolism of NE-100, metoprolol, clarithromycin (CAM), lornoxicam and tenoxicam were predicted from in vitro data with recombinant cytochorme P450s (CYPs) using relative activity factor (RAF) and then compared with CLint-HLM observed in human liver microsomes (HLM). The predicted CLint-HLM-total correlated well with the observed CLint-HLM in HLM. When oral clearances (CLoral) of low-clearance drugs such as metoprolol, CAM, lornoxicam and tenoxicam were predicted from the in vitro data using four physiological models (well-stirred, parallel tube, distributed and dispersion models), the predicted CLoral corresponded well with the observed CLoral in vivo and were similar among the four models. For a high-clearance drug, the predicted CLoral of NE-100 in extensive CYP2D6 metabolizers (EMs) was substantially different between individual models, although the predicted CLoral in a poor metabolizer of CYP2D6 (PMs) was similar. The CLoral ratio of NE-100 between the EMs and the PMs predicted from the dispersion model, which leads to a reliable prediction for the high-clearance drug, was 48.4, but the ratio decreased depending on the increase of the NE-100 plasma concentration. The results suggest that the CLoral decrease in the EMs is caused by saturation of NE-100 metabolism mediated by CYP2D6 and is based on increases in plasma NE-100 concentrations dependent on the dose of NE-100. The study suggests that the RAF and the in vitro–in vivo scaling approaches are useful for predicting CLoral from in vitro data with recombinant CYPs without using HLM and hepatocytes.