In vitro/in vivo scaling of alprazolam metabolism by CYP3A4 and CYP3A5 in humans
In vitro/in vivo scaling of alprazolam metabolism by CYP3A4 and CYP3A5 in humans
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DOI：
10.1002/bdd.261
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发表时间：
2001-03-01
影响因子：
2.1
通讯作者：
Sugiyama, Y
中科院分区：
文献类型：
--
作者：
Hirota, N;Ito, K;Sugiyama, Y
我们试图预测阿普唑仑的体内代谢清除率，从体外代谢研究中使用人肝微粒体和人重组体。在10份人肝微粒体样品中，观察到4-羟基化的固有清除率（克林特）与CYP 3A 4含量之间以及α-羟基化的克林特与CYP 3A 5含量之间存在良好的相关性。使用在昆虫细胞中表达的重组CYP 3A 4亚型，在4-羟基化的情况下，CYP 3A 4的克林特比CYP 3A 5的克林特高约2倍。然而，在α-羟基化的情况下，CYP 3A 5的克林特比CYP 3A 4的克林特高约3倍。随着细胞色素B（5）添加量的增加，4-和α-羟基化的代谢率增加，其最大值比不含细胞色素B（5）的代谢率高3- 4倍。使用人肝微粒体和CYP 3A 4和CYP 3A 5重组体的体外研究预测的克林特体内值在文献数据计算的观察值的2.5倍范围内。使用3份人肝微粒体样本获得的平均克林特值（4-和α-羟基化总和）比使用来自相同供体的3份小肠微粒体样本获得的平均CLint值高4倍，表明肠道代谢对阿普唑仑处置的贡献较小。据报告，与酮康唑联合给药后阿普唑仑的血浆浓度-时间曲线下面积（AUC）增加，根据体外Ki值和报告的酮康唑药代动力学参数预测的增加幅度为2.30-2.45，接近体内观察到的值（3.19）。考虑到西咪替丁主动转运至肝脏，西咪替丁的AUC增加的定量预测也是成功的（1.73-1.79 vs 1.58-1.64）。总之，我们已经成功地进行了体外/体内缩放阿普唑仑代谢使用人肝微粒体和人CYP 3A 4和CYP 3A 5重组体。版权所有（C）2001约翰威利父子有限公司
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.