In vitro/in vivo scaling of alprazolam metabolism by CYP3A4 and CYP3A5 in humans

被引:63
作者
Hirota, N
Ito, K
Iwatsubo, T
Green, CE
Tyson, CA
Shimada, N
Suzuki, H
Sugiyama, Y
机构
[1] Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan
[2] Kitasato Univ, Sch Pharmaceut Sci, Minato Ku, Tokyo 1088641, Japan
[3] Yamanouchi Pharmaceut Co Ltd, Inst Drug Dev Res, Drug Metab Labs, Itabashi Ku, Tokyo 1748511, Japan
[4] SRI Int, Toxicol Lab, Menlo Pk, CA 94025 USA
[5] Daiichi Pure Chem Co Ltd, Corp Planning Off, Chuo Ku, Tokyo 1030027, Japan
关键词
alprazolam; metabolism; in vitro/in vivo scaling; CYP3A4; CYP3A5;
D O I
10.1002/bdd.261
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
We attempted to predict the in vivo metabolic clearance of alprazolam from in vitro metabolic studies using human liver microsomes and human CYP recombinants. Good correlations were observed between the intrinsic clearance (CLint) for 4-hydroxylation and CYP3A4 content and between the CLint for alpha -hydroxylation and CYP3A5 content in ten human liver microsomal samples. Using the recombinant CYP isoforms expressed in insect cells, the CLint for CYP3A4 was about 2-fold higher than the CLint for CYP3A5 in the case of 4-hydroxylation. However, the CLint for CYP3A5 was about 3-fold higher than the CLint for CYP3A4 in the case of alpha -hydroxylation. The metabolic rates for 4- and alpha -hydroxylation increased as the added amount of cytochrome b(5) increased, and their maximum values were 3- to 4-fold higher than those without cytochrome b(5). The values of CLint, in vivo predicted from in vitro studies using human liver microsomes and CYP3A4 and CYP3A5 recombinants were within 2.5 times of the observed value calculated from literature data. The average CLint value (sum of 4- and alpha -hydroxylation) obtained using three human liver microsomal samples was 4-fold higher than that obtained using three small intestinal microsomal samples from the same donors, indicating the minor contribution of intestinal metabolism to alprazolam disposition. The area under the plasma concentration-time curve (AUC) of alprazolam is reported to increase following co-administration of ketoconazole and the magnitude of the increase predicted from the in vitro K-i values and reported pharmacokinetic parameters of ketoconazole was 2.30-2.45, which is close to the value observed in vivo (3.19). A quantitative prediction of the AUC increase by cimetidine was also successful (1.73-1.79 vs 1.58-1.64), considering the active transport of cimetidine into the liver. In conclusion, we have succeeded in carrying out an in vitro/in vivo scaling of alprazolam metabolism using human liver microsomes and human CYP3A4 and CYP3A5 recombinants. Copyright (C) 2001 John Wiley & Sons, Ltd.
引用
收藏
页码:53 / 71
页数:19
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