Prediction of oral clearance from in vitro metabolic data using recombinant CYPs: comparison among well-stirred, parallel-tube, distributed and dispersion models.
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 CLoralin 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.
Yamamoto
T
T
Drug Metabolism Laboratory, Medicinal Development Research Laboratories, Taisho Pharmaceutical Co., Ltd, Saitama, Japan. takahito.yamamoto@po.rd.taisho.co.jp
Itoga
H
H
Kohno
Y
Y
Nagata
K
K
Yamazoe
Y
Y
D000284:Administration, Oral; D000818:Animals; D000840:Anisoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D017291:Clarithromycin / Q000008:administration & dosage / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008790:Metoprolol / Q000008:administration & dosage / Q000493:pharmacokinetics; D008954:Models, Biological; D010894:Piroxicam / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D011237:Predictive Value of Tests; D011437:Propylamines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D000840:Anisoles; D011437:Propylamines; D011994:Recombinant Proteins; D010894:Piroxicam; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C059451:lornoxicam; D008790:Metoprolol; D017291:Clarithromycin; C032801:tenoxicam