Inhibitory effect of stiripentol on carbamazepine and saquinavir metabolism in human
Inhibitory effect of stiripentol on carbamazepine and saquinavir metabolism in human
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DOI：
10.1046/j.0306-5251.2003.01919.x
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发表时间：
2003-11-01
影响因子：
3.4
通讯作者：
Pons, G
中科院分区：
文献类型：
--
作者：
Cazali, N;Tran, A;Pons, G
目的研究新型抗惊厥药司替戊醇（stiripentol）对CYP 3A 4底物卡马西平和沙奎那韦代谢的抑制作用。方法采用人肝微粒体和cDNA表达的CYP 3A 4酶进行体外实验。结果卡马西平在人肝微粒体中生物转化为10，11-环氧化合物（Vmax = 10.3 nmol min（-1）nmol（-1）P450，表观Km = 362 μ m），cDNA表达的CYP 3A 4（Vmax = 1.17 nmol min（-1）nmol（-1）P450，表观Km = 119 mum）和CYP 2C 8（V-max = 0.669 nmol min（-1）nmol（-1）P450，表观Km = 757 μ m）被司替戊醇抑制（IC 50分别为14、5.1、37 μ M，表观Ki分别为3.7、2.5、35 μ m）。沙奎那韦通过人肝微粒体向其主要代谢物M7的生物转化（Vmax = 5.7 nmol min（-1）nmol（-1）P450，表观Km = 0.79 μ m）被司替戊醇抑制（IC 50 163 μ M，表观Ki 86 μ m）。卡马西平与司替戊醇联用后，卡马西平/环氧化物血药浓度比下降65%。司替戊醇的体内表观Ki范围为10.5至41.4 μ m。沙奎那韦的药代动力学没有修改司替戊醇在健康成人。沙奎那韦的Cmax和AUC在安慰剂和司替戊醇治疗期之间差异的95%可信区间分别为（-39.8，39.8）和（-33.2，112）。相反，司替戊醇是体外和体内癫痫患者卡马西平10，11-环氧化物形成的有效抑制剂。
Aims To characterize the in vitro and in vivo inhibitory effect of stiripentol, a new anticonvulsant, on the metabolism of carbamazepine and saquinavir, which are substrates of CYP3A4.Methods Human liver microsomes and cDNA-expressed CYP enzymes were used for the in vitro experiments. Pharmacokinetic data from epileptic children and healthy adults were used for the carbamazepine and saquinavir in vivo studies, respectively.Results Carbamazepine biotransformation to its 10,11-epoxide by human liver microsomes (V-max = 10.3 nmol min(-1) nmol(-1) P450, apparent Km = 362 mum), cDNA-expressed CYP3A4 (V-max = 1.17 nmol min(-1) nmol(-1) P450, apparent Km = 119 mum) and CYP2C8 (V-max = 0.669 nmol min(-1) nmol(-1) P450, apparent Km = 757 mum) was inhibited by stiripentol (IC50 14, 5.1, 37 muM and apparent Ki 3.7, 2.5, 35 mum, respectively). Saquinavir biotransformation to its major metabolite M7 by human liver microsomes (V-max = 5.7 nmol min(-1) nmol(-1) P450, apparent Km = 0.79 mum) was inhibited by stiripentol (IC50 163 muM, apparent Ki 86 mum). In epileptic children treated with carbamazepine and stiripentol, the plasma concentration ratio of carbamazepine epoxide/carbamazepine was decreased by 65%. The in vivo apparent Ki for stiripentol ranged from 10.5 to 41.4 mum. The pharmacokinetics of saquinavir was not modified by stiripentol in healthy adults. The 95% confidence intervals for the difference for C-max and AUC of saquinavir between the placebo and stiripentol phase were (-39.8, 39.8) and (-33.2, 112), respectively.Conclusions These results showed that stiripentol was a weak inhibitor of saquinavir metabolism both in vitro and in vivo. In contrast, stiripentol is a potent inhibitor of carbamazepine 10,11-epoxide formation in vitro and in vivo in epileptic patients.