Prediction of oral clearance from in vitro metabolic data using recombinant CYPs: Comparison among well-stirred, parallel-tube, distributed and dispersion models

Abstract

Intrinsic clearances (CL_{int-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 CL_int-HLM observed in human liver microsomes (HLM). The predicted CL_{int-HLM-total} correlated well with the observed CL_int-HLM in HLM. When oral clearances (CL_oral) 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 CL_oral corresponded well with the observed CL_oral in vivo and were similar among the four models. For a high-clearance drug, the predicted CL_oral of NE-100 in extensive CYP2D6 metabolizers (EMs) was substantially different between individual models, although the predicted CL_oral in a poor metabolizer of CYP2D6 (PMs) was similar. The CL_oral 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 CL_oral 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 CL_oral from in vitro data with recombinant CYPs without using HLM and hepatocytes.

• NE-100
• cytochrome P450
• prediction
• clearance
• in vitro–in vivo scaling