卡马西平
CYP2C19型
苯妥英钠
药代动力学
苯巴比妥
药理学
唑尼沙胺
CYP2D6型
人口
药物遗传学
化学
抗惊厥药
非金属
药物相互作用
医学
内科学
基因型
细胞色素P450
癫痫
新陈代谢
生物化学
精神科
托吡酯
基因
环境卫生
作者
Yusuke Okada,Takayuki Shioiri,Takateru Ishitsu,Atsuko Wanibuchi,Naozumi Hashimoto,Yoko Higa,Kazuko Nakagawa
出处
期刊:Therapeutic Drug Monitoring
[Ovid Technologies (Wolters Kluwer)]
日期:2008-08-01
卷期号:30 (4): 540-543
被引量:30
标识
DOI:10.1097/ftd.0b013e31817d842a
摘要
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.
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