Individual therapy due to CYP genetic polymorphisms in patient with epilepsy

本项目的目的是通过表征癫痫患者的个体基因多态性来避免药物相互作用引起的副作用。首先，我们建立了大鼠血液和肝脏中CYP3A13和CYP2C11的实时荧光定量聚合酶链式反应分析方法。为验证卡马西平作为代谢能力生物标志物的有效性，分别于末次给予卡马西平(50 mg/kg，浓度2周)后3、6、12、24小时检测细胞色素P450的mRNA表达和蛋白含量。细胞色素P450的mRNA表达和蛋白含量呈现不同的时间曲线。血液中未检测到CYP2C11基因，不能作为有用的生物标志物。卡马西平给药后3h，肝脏和血液中细胞色素P450 m RNA的含量呈显著正相关。因此，适宜的采样时间为给药后3小时。以卡马西平的主要代谢物环氧化卡马西平与卡马西平的AUC(0~3小时)之比评价药物的代谢能力。结果表明，代谢能力与细胞色素P3A13基因表达或蛋白含量的相关性受剂量的影响。本项目所获得的结果为建议每个患者的剂量计划提供了有用的信息。

The purpose of this project is to avoid the side effects due to drug interaction by characterizing the individual gene polymorphisms in patients with epilepsy. First, we developed the real-time PCR analysis for CYP3A13 and CYP2C11 in blood or liver in rat. To verify the usefulness as biomarker for metabolic ability, mRNA expression and protein content of CYPs was assayed at 3, 6, 12, 24 hr after final administration of carbamazepin ( 50 mg/kg, concecutive 2 weeks) in rat. The mRNA expression and protein content of CYPs showed different time profile. The CYP2C11 mRNA in blood was not detectable, thereof was not useful biomarker. The liver and blood content of CYPmRNA at 3 hr after carbamazepin administration showed a significant correlation. Therefore, it was expected that suitable sampling time was 3 hr after administration. The metabolic ability was estimated by the ratio of AUC (0-3 hr) of carbamazepin-epoxide, main metabolite to carbamazepin. It was clarified that the correlation between metabolic ability and mRNA expression or protein content of CYP3A13 was influenced by the dose. The findings obtained in this project provide a useful information to recommend the dosage planning every individual patient.