癫痫患者细胞色素P450 2C19* 2基因型与奥卡西平活性代谢物浓度相关性研究

Relationship between cytochromes P450 2C19* 2 genotype and the concentration of the active oxcarbazepine metabolite in pediatric patients with epilepsy

目的分析细胞色素P450 2C19~*2(CYP2C19~*2)基因型与奥卡西平活性代谢产物浓度在癫痫患者群体中的相关性。方法纳入65例使用奥卡西平进行治疗的16岁以下癫痫患者,在奥卡西平血药浓度达稳后(第7次给药后)取谷浓度血,用反相高效液相色谱法(RP-HPLC)测定奥卡西平活性代谢产物10,11-二氢-10-羟基卡马西平(MHD)浓度,用基于序列特异性引物的聚合酶链式反应(PCR-RFLP)和凝胶电泳法测定CYP2C19~*2基因型。用单因素方差分析对所获数据进行组间差异检测,用多元线性回归法对性别、年龄、日剂量、公斤体重给药量、基因型和血药浓度的相关性进行多因素分析。结果 65例癫痫患者中CYP2C19~*2位点纯合野生型有(~*1/~*1)35例,MHD浓度为(17.41±7.58)μg·mL^(-1);杂合突变型(~*1/~*2)22例,MHD浓度为(19.38±9.74)μg·mL^(-1);纯合突变型(~*2/~*2)8例,MHD浓度为(21.68±7.69)μg·mL^(-1)。3种基因型的MHD浓度比较,差异均无统计学意义(P>0.05)。多因素分析显示,日剂量与MHD血药浓度存在显著相关性(P<0.05),其他因素均无显著相关性。结论不同CYP2C19~*2基因型癫痫患者的MHD浓度不存在显著性差异,建议对于儿童患者使用奥卡西平,进行血药浓度监测比基因检测更适合。

Objective To evaluate the correlation between cytochromes P450 2C19＊ 2（CYP2C19＊ 2） genotype and the concentration of the active oxcarbazepine metabolite in patients with epilepsy.Methods We included 65 patients with epilepsy that used oxcarbazepine for treatment who were under 16 years old.Then collecte blood after steady state（after the 7 dose） and use reversed-phase high-performance liquid chromatography（RP-HPLC） to determine the trough concentration of monohydroxycarbazepine（MHD） which is an active oxcarbazepine metabolite.Polymerase chain reaction-restriction fragment length polymorphism（PCR-RFLP） and agarose gel electrophoresis were used to determine CYP2C19＊ 2 genotype.The differences between the groups were tested by using single factor analysis of variance;Multi factors analysis was tested by using multiple linear regression model and gender,age,daily dosage,dosage by weight and genotype were considered as parameters.Results Of 65 patients with epilepsy,35 were homozygous wild-type（＊ 1/＊ 1） with an average MHD concentration（17.41 ±7.58）μg · mL^-1;22 were heterozygote（＊ 1/＊ 2） with an average MHD concentration（21.68 ±7.69） μg · mL^-1;8 were homozygous mutation（＊2/＊ 2） with an average MHD concentration（19.38 ±9.74） μg · mL^-1.The differences of plasma concentration of MHD between three genotypes are not statistically significant（P〈0.05）;In multiple linear regression model,the daily dose was positively related to MHD concentration（P〈0.05）,and others are not.Conclusion There is no significant difference between CYP2C19＊ 2 genotype and the concentration of MHD in patients with epilepsy.For pediatric patients treated with oxcarbazepine,therapeutic drug monitoring is more recommended than genetic testing.