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

Xenobiotica, ISSN: 0049-8254, Vol: 35, Issue: 6, Page: 627-646
2005
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Article Description

Intrinsic clearances (CL) 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 observed in human liver microsomes (HLM). The predicted CL correlated well with the observed CL in HLM. When oral clearances (CL) 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 corresponded well with the observed CL in vivo and were similar among the four models. For a high-clearance drug, the predicted CL of NE-100 in extensive CYP2D6 metabolizers (EMs) was substantially different between individual models, although the predicted CL in a poor metabolizer of CYP2D6 (PMs) was similar. The CL 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 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 from in vitro data with recombinant CYPs without using HLM and hepatocytes. © 2005 Taylor & Francis.

Bibliographic Details

T. Yamamoto; H. Itoga; Y. Kohno; K. Nagata; Y. Yamazoe

Informa UK Limited

Biochemistry, Genetics and Molecular Biology; Pharmacology, Toxicology and Pharmaceutics; Environmental Science

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