Population Estimation Regarding the Effects of Cytochrome P450 2C19 and 3A5 Polymorphisms on Zonisamide Clearance
Population Estimation Regarding the Effects of Cytochrome P450 2C19 and 3A5 Polymorphisms on Zonisamide Clearance
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关于细胞色素 P450 2C19 和 3A5 多态性对唑尼沙胺清除率影响的群体估计
DOI：
10.1097/ftd.0b013e31817d842a
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发表时间：
2008
影响因子：
2.5
通讯作者：
K. Nakagawa
中科院分区：
文献类型：
--
作者：
Yusuke Okada;Takayuki Seo;T. Ishitsu;Atsuko Wanibuchi;Nami Hashimoto;Yoko Higa;K. Nakagawa
我们的目的是评估细胞色素P450（CYP）2C 19和CYP 3A 5多态性对唑尼沙胺（ZNS）清除率的影响。从99名日本癫痫患者中获得的282个稳态ZNS浓度的药代动力学采用非线性混合效应建模程序进行，使用一级消除的一室开放药代动力学模型。筛选的协变量包括总体重、性别、ZNS日剂量、CYP 2C 19和CYP 3A 5基因型以及合并使用的抗癫痫药物。ZNS表观清除率的最终模型如下：其中CL为ZNS的表观口服清除率，DOSE为ZNS每日剂量，如果分别携带一个或两个CYP 2C 19缺陷型等位基因，则CYP 2C 19杂合快代谢型（EM）或CYP 2C 19弱代谢型（PM）等于1;否则为0。如果卡马西平、苯妥英或苯巴比妥分别联合给药，则卡马西平（CBZ）、苯妥英（PHT）或苯巴比妥（PB）等于1;否则等于0。ηCL是正态分布的独立随机误差，均值为零，方差等于ω CL 2。ZNS的CL在CYP 2C 19杂合子快代谢型和慢代谢型中分别比纯合子快代谢型低16%和30%（P < 0.001）。未发现CYP 3A 5多态性的影响。卡马西平、苯妥英钠或苯巴比妥联合给药使ZNS的CL增加24%至29%。本报告表明，CYP 2C 19基因型影响ZNS代谢在日本癫痫患者。这些变化的临床相关性仍有待于在未来的研究中探索。
We aimed to evaluate the effects of cytochrome P450 (CYP) 2C19 and CYP3A5 polymorphisms on zonisamide (ZNS) clearance. The pharmacokinetics of the 282 ZNS concentrations at a steady state obtained from 99 Japanese epileptic patients was performed with a nonlinear mixed-effect modeling program, using a one-compartment open pharmacokinetic model with first-order elimination. The covariates screened included the total body weight, gender, ZNS daily dose, CYP2C19 and CYP3A5 genotypes, and the coadministered antiepileptic drugs. The final model of ZNS apparent clearance was as follows: where CL is the apparent oral clearance of ZNS, DOSE is ZNS daily dose, and CYP2C19 heterozygous extensive metabolizer (EM) or CYP2C19 poor metabolizer (PM) is equal to 1 if one or two CYP2C19-defective alleles are carried, respectively; otherwise, it is 0. Carbamazepine (CBZ), phenytoin (PHT), or phenobarbital (PB) is equal to 1 if carbamazepine, phenytoin, or phenobarbital is coadministered, respectively; otherwise, it is 0. ηCL is the independent random error distributed normally with the mean zero and variance equal to ωCL2. The CL of ZNS was lower in the CYP2C19 heterozygous extensive metabolizers and poor metabolizers than in the homozygous extensive metabolizers by 16% and 30%, respectively (P < 0.001). An effect of CYP3A5 polymorphisms was not identified. The coadministration of carbamazepine, phenytoin, or phenobarbital increased the CL of ZNS by 24% to 29%. This report demonstrates that the CYP2C19 genotype affects the ZNS metabolism in Japanese epileptic subjects. The clinical relevance of these changes remains to be explored in future studies.