CBZ和CBZE血药浓度个体差异与CYP3A5~＊3基因多态性的相关性分析

Association of individual different plasma Carbamazepine and 10,11-Carbamazepine Epoxide concentration with CYP3A5~＊3 gene polymorphismV

目的探讨卡马西平(CBZ)药物代谢个体差异性的遗传学机制,从而指导临床抗癫痫治疗中的个体化用药。方法选取确诊为癫痫并适用CBZ的患者58例。首先利用PCR技术扩增患者外周血中包含等位基因CYP3A5*3(rs776746)的基因片段;其次采用基因测序法确定该等位基因各基因型的分布,将包含原始碱基(A)的基因序列归为A组,而将只含有突变碱基(C)的基因序列归为B组;最后,应用高效液相色谱法测定两组患者外周血中CBZ及其代谢产物10,11-环氧化卡马西平(CBZE)的血药浓度。采用t检验,比较A、B两组患者CBZ和CBZE血药浓度的差异。结果 A组患者CBZ的浓度明显低于B组(P<0.01);A组患者CBZE的浓度明显高于B组(P<0.05)。CYP3A5*3的基因多态性与CBZ及其代谢产物CBZE的血药浓度相关,CYP3A5*3突变纯合型CBZ代谢减慢,血药浓度相应增高,应给予相对小剂量的CBZ,以提高临床用药的安全性。结论 CYP3A5*3的基因多态性可能作为临床治疗中CBZ剂量个体化的一项重要参考依据。

Objective To explore the genetic mechanism of the individual differences in carbamazepine metabolism,and then to provide a guidance for the individual medication in the clinical practice of the anti-epileptic treatment.Methods 58 cases of the out-patients and in-patients in the Department of Neurology with epilepsy from March 2007 to December 2007 were enrolled in the study,who were suitable for CBZ.Experimental procedures were as follows：Firstly,PCR amplification of CYP3A5 gene fragments contain allele CYP3A5＊3（rs776746）was proceeded;Secondly,the allele distribution of the genotypes was determined via gene sequencing;The results were divided into two groups according to the genotypes.The ones which containing the original base A were classified as Group A,and the others which containing only mutation base C were classified as Group B.Lastly,Carbamazepine and its metabolite CBZE was detected by HPLC method.T-test was employed to compare the differences of CBZ and CBZE plasma concentration between Group A and B statistically.Results The plasma concentration of CBZ of group A was much lower than that of group B（P0.01）.The plasma concentration of CBZE of group A was much higher than that of group B（P0.05）.The CYP3A5＊3 gene polymorphism correlates with the plasma concentration of CBZ and its metabolite,CBZE.The metabolism of CBZ in the patients with homozygous mutant-type CYP3A5＊3 gene was relatively slower,thus the plasma concentration was correspondingly higher.So a smaller dose of CBZ should be given to them,in order to improve the safeness in clinical medication.Conclusion The CYP3A5＊3 gene polymorphism could serve as a criteria for an assessment in individual anti-epileptic treatment for the clinical carbamazepine dose medication.