Prediction of in vivo Human Hepatic Clearance in Drug Discovery.
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Accession number;00A0997684
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| Title;Prediction of in vivo Human Hepatic Clearance in Drug Discovery. |
| Author;
NARITOMI YOICHI
(Fujisawa Pharm. Co., Ltd.)
TERASHITA SHIGEYUKI
(Fujisawa Pharm. Co., Ltd.)
KIMURA SUMIHISA
(Fujisawa Pharm. Co., Ltd.)
KAGAYAMA AKIRA
(Fujisawa Pharm. Co., Ltd.)
SUGIYAMA YUICHI
(Univ. of Tokyo, Fac. of Pharm. Sci.)
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Journal Title;Xenobiotic Metabolism and Disposition
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Journal Code:X0758A
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ISSN:0916-1139
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VOL.15;NO.Supplement;PAGE.S120-S121(2000)
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| Figure&Table&Reference;FIG.2 |
| Pub. Country;Japan |
| Language;Japanese |
| Abstract;We have investigated a quantitative prediction of in vivo human hepatic clearance from in vitro experiments. In vivo intrinsic clearance (CLX(X=int,in vivo)) were compared with in vitro intrinsic clearance (CLY(Y=int,in vitro)) from in vitro metabolism data obtained by using liver microsomes focusing on P450 metabolism in rats, dogs and humans. The scaling factor (CLX(X=int,in vivo)/CLY(Y=int,in vitro)) were different among the model compounds, while most of the animal scaling factors were within 2-fold of the values in humans. When human CLY(Y=int,in vitro) values were compared with the actual CLX(X=int,in vivo), correlations were not necessarily good. By contrast, using human CLY(Y=int, in vitro) corrected with the animal scaling factor yielded better predictions of CLX(X=int, in vivo) that were mostly within 2-fold of actual values. Further, CLX(X=int, in vivo) were compared with CLY(Y=int, in vitro) from in vitro metabolism data obtained by using rat fresh and human cryopreserved hepatocytes. Human CLY(Y=int, in vitro) corrected with the rat scaling factor yielded good predictions of CLX(X=int, in vivo) that were mostly less than several-fold of actual values. This method thus provides a more reliable prediction of human hepatic clearance and will be useful in drug discovery. (author abst.) |
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