中国癫痫患者细胞色素P4503A亚家族基因多态性对卡马西平及环氧化卡马西平代谢率的影响

Effect of Cytochrome P4503A Subfamily Gene Polymorphism on the Metabolic Rate of Carbamazepine and Cyclooxygenated Carbamazepine in Chinese Epilepsy Patients

目的探讨不同CYP3A4基因型患者中卡马西平(CBZ)和环氧化卡马西平(CBZE)不同的代谢特点,以指导临床抗癫痫治疗中个体化用药。方法选取58例适用CBZ的癫痫患者血样本,运用多聚酶链式反应(PCR)及测序方法,检测CYP3A4基因的变异。按基因位点发生的杂合与纯合,患者可分为基因杂合子弱代谢者(M型)和基因纯合子快代谢者(w型)。运用高效液相色谱(HPLC)法及血药浓度监测仪测定外周血中CBZ和CBZE的血药浓度。比较M型和w型两组患者CBZ和CBZE血药浓度的差异。结果在58例样本测序后发现CYP3A4基因位于内含子10中的一个SNP(rs2242480),其中M型频率为32.76%(19例),未发现外显子的突变。w型携带者CBZ及CBZE血药浓度的平均值明显低于M型CBZ及CBZE血药浓度的平均值。CBZ血药浓度值基因型比较,差异有统计学意义(t=-5.566,P=0.000)。结论CYP3A4突变等位基因携带者CBZ代谢减慢,相应CBZ和CBZE血药浓度增高,应相对给予小剂量CBZ,提高临床用药的可靠性、安全性和有效性。

Objective To investigate the different metabolic characteristics of cassipine(CBZ)and cassipine(CBZE)in patients with different CYP3A4 genotypes in order to guide the individualization of antiepileptic therapy.Methods Blood samples from 58 patients with epilepsy using CBZ were taken.PCR and sequencing methods were used to detect the variation of CYP3A4 gene.According to the heterozygous and homozygous that occur at the gene site,the patient can be divided into the weak metabolite(M type)of the gene heterozygous and the fast metabolite of the gene homozygous(w type).The blood concentration of CBZ and CBZE in peripheral blood was determined by HPLC and blood concentration monitor.The difference of blood drug concentration of CBZ and CBZE was compared between the two groups.Results After the sequencing of 58 samples,the CYP3A4 gene was found to be located in one SNP(rs2242480)in intron 10,in which the frequency of M type was 32.76%(19 cases),and no mutation of exon was found.The average blood concentration of the w carriers,CBZ and CBZE,was significantly lower than that of the M type,CBZ and CBZE.The genotype comparison of CBZ blood drug concentration has a significant statistical difference(t=-5.566,P=0.000).Conclusion In the carrier of CYP3A4 mutant allele,CBZ metabolism was slowed down and CBZ and CBZE plasma concentrations were increased.the relative low dose of CBZ was given to improve the reliability,safety and efficacy of clinical medication.