CYP2C9、CYP2A6基因多态性对丙戊酸钠血药浓度的影响

Effects of CYP2C9 and CYP2A6 genetic polymorphisms on plasma concentrations of sodium valproate

目的:研究CYP2C9、CYP2A6基因多态性对癫痫患儿丙戊酸钠血药浓度的影响。方法:收集单用丙戊酸钠治疗的癫痫患儿,应用荧光偏振免疫法测定丙戊酸钠血药浓度;分别采用直接测序法、巢式PCR法检测CYP2C9、CYP2A6的基因型;应用单因素方差分析研究基因多态性对丙戊酸钠血药浓度的影响。结果:83例癫痫患儿根据CYP2C9、CYP2A6基因型分为3组:强代谢组(CYP2C9*1*1合并CYP2A6*1*1)、中代谢组(CYP2C9*1*3合并CYP2A6*1*1或CYP2C9*1*1合并CYP2A6*1*4)和弱代谢组(CYP2C9*1*3合并CYP2A6*1*4或CYP2A6*4*4),3组分布频率分别为73.5%、24.1%和2.4%。中代谢组的标准化血药浓度显著高于高代谢组(P<0.05),低代谢组的标准化血药浓度均数比其他两组高,但差异无统计学意义(P>0.05)。结论:CYP2C9、CYP2A6的基因多态性能影响丙戊酸钠血药浓度,可通过检测基因型选择合适的丙戊酸钠初始剂量。

Objective： To investigate the effects of CYP2C9 and CYP2A6 genetic polymorphisms on plasma concentrations of sodi- um valproate （VPA） in the epileptic children. Methods： Epileptic children treated with sodium valproate only were collected in our study. Fluorescence polarization immunoassay was performed to measure plasma concentrations of sodium valproate. Direct sequencing and nest-PCR were applied to identify the genotypes of CYP2C9 and CYP2A6. One-way ANOVA was performed to analyze the influence of the polymorphisms on plasma concentrations of sodium valproate. Results： Patients were divided into 3 groups according to the genotypes of CYP2C9 and CYP2A6： extensive metabolizers （EM, CYP2C9＊1＊1 ＆ CYP2A6＊1＊1）, intermediate metabolizers （IM, CYP2C9＊1＊3 ＆ CYP2A6＊1＊1 or CYP2C9＊1＊1 ＆ CYP2A6＊1＊4）, and poor metabolizers （PM, CYP2C9＊1＊3 ＆ CYP2A6＊1＊4 or CYP2A6＊4＊4）, and the frequencies of the three groups were 73.5%, 24.1%, and 2.4%, respectively. The standardized blood drug concentration of IM was significantly higher than that of EM （P〈0.05）. The mean of standardized blood drug concentration of PM was higher than the others, but there were no significant differences between them （P〉0.05）. Conclusion： The plasma concentrations of sodium valproate can be affected by the polymorphisms of CYP2C9 and CYP2A6. Chnicians can choose appropriate initial dosage by detecting the genotypes.