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Vol. 29, Issue 10, 1316-1324, October 2001
Biopharmaceutical and Pharmacokinetic Research Laboratories,
Fujisawa Pharmaceutical Co., Ltd., Kashima, Yodogawa-ku, Osaka, Japan
(Y.N., S.T., S.K., A.S., A.K.); and Graduate School of Pharmaceutical
Sciences, the University of Tokyo, Hongo, Bunkyou-ku, Tokyo, Japan
(Y.S.)
We investigated the quantitative prediction of human hepatic
metabolic clearance from in vitro experiments focusing on cytochrome P450 metabolism with eight model compounds, FK1052, FK480,
zolpidem, omeprazole, nicardipine, nilvadipine, diazepam, and
diltiazem. For the compounds, in vivo human hepatic extraction
ratios ranged widely from 0.03 to 0.87. In vitro and in vivo hepatic
intrinsic clearance (CLint) values for each compound were
measured and calculated in rats and/or dogs and humans. CLint,in
vitro was determined from a substrate disappearance rate at 1 µM in hepatic microsomes, which was a useful method. CLint,in
vivo was calculated from in vivo pharmacokinetic data using
three frequent mathematical models (the well stirred, parallel-tube,
and dispersion models). The human scaling factor values (CLint,in
vivo/CLint,in vitro) showed marked difference among
the model compounds (0.3-26.6-fold). On the other hand, most of the
animal scaling factors were within 2-fold of the values in humans,
suggesting that scaling factor values were similar in the different
animal species. When human CLint,in vitro values were
compared with the actual CLint,in vivo, correlation was not
necessarily good. By contrast, using human CLint,in vitro
corrected with the rat and/or dog scaling factors yielded better
predictions of CLint,in vivo that were mostly within 2-fold
of the actual values. Furthermore, successful predictions of human
CLoral and hepatic extraction ratio (EH) were
obtained by use of the human CLint,in vitro corrected with
animal scaling factors. The new variant method is a simple one,
incorporating additional information from animal studies and providing
a more reliable prediction of human hepatic clearance.
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