细胞色素P450酶2A6、2B6、2C9及2C19基因多态性对丙戊酸钠血药浓度的影响  

Effects of cytochrome P450 isozymes 2A6, 2B6, 2C9 and 2C19 genetic polymorphisms on plasma concentration of sodium valproate

作　　者：廖清船[1] 史菁菁[2] 张永[1] 李晓蕾 刘思婷[1] 仇锦春[1] 

机构地区：[1]南京医科大学附属南京儿童医院药剂科,南京210008 [2]中国药科大学临床药学教研室 [3]上海儿童医学中心药剂科

出　　处：《中华神经科杂志》2013年第2期82-86,共5页Chinese Journal of Neurology

基　　金：南京市医学科技发展项目（YKK09077）;南京市2011年度科技发展计划资助项目（药学项目：2011YX016）

摘　　要：目的探讨细胞色素P450酶2A6（CYP2A6）、286（CYP286）、2C9（CYP2C9）和2C19（CYP2C19）基因多态性对丙戊酸钠血药浓度的影响。方法选择单药服用丙戊酸钠的癫痫患儿131例，应用多重PCR方法对CYP2A6＊4基因多态性进行检测，应用PCR．连接酶检测反应技术对CYP286。6、CYP2C9＊2、CYP2C9＊3、CYP2C19＊2和CYP2C19＊3基因多态性进行检测，应用均相酶放大免疫分析法测定丙戊酸钠血药浓度，采用单因素方差分析方法或t检验进行统计学分析。结果患儿根据CYP2C9、CYP2C19基因型分为4组：G1组（CYP2C9和CYP2C19均为强代谢者）、G2组（CYP2C19中间代谢者）、G3组（CYP2C19弱代谢者）和G4（CYP2C9弱代谢者）；G3（3．70±0．95）、c4组（4．35±1．48）标准化血药浓度显著高于G1组（2．57±1．30，t=3．056、4．490，均P〈0．01）和G2组（2．76±1．19，t=2．827、4．462，均P〈0．01）；G3（19．46±5．20）、G4组（19．30±7．67）丙戊酸钠剂量（mg／d）显著低于G1组（24．10±6．97，t=2．359、2．297，均P〈0．05）。未发现突变型CYP2A6’4和CYP286’6对丙戊酸钠剂量和丙戊酸钠标准化血药浓度的影响。结论CYP2C9和CYP2C19基因多态性会影响丙戊酸钠血药浓度，弱代谢（G3和G4组）的患JIA]~用丙戊酸钠应适当减少剂量。Objective To investigate the influences of the functional polymorphisms of cytochrome P450 isozymes 2A6 （ CYP2A6 ）, 2B6 （ CYP2B6 ）, 2C9 （ CYP2C9 ）, and 2C19 （ CYP2C19 ） on plasma concentration of sodium valproate. Methods A total of 131 Chinese children with epilepsy receiving sodium valproate after a period of more than 5 half-time were recruited. The genotypes of CYP2A6 were detected by multiplex polymerase chain reaction （PCR）, and the genotypes of CYP2B6, CYP2C9, and CYP2C19 were detected by PCR-ligase detection reaction. Enzyme-multiplied immunoassay technique was used to measure the plasma concentration of sodium valproate. The association between the polymorphisms and the plasma concentration of sodium valproate were analyzed by one-way ANOVA or Student＇ s t-test. Results Patients were divided into 4 groups according to the genotyping results of CYP2C9 and CYP2C19 （ G1 ： extensive metabolizers in both CYP2C9 and CYP2C19; G2：CYP2C19 intermediate metabolizers; G3：CYP2C19 poor metabolizers; G4：CYP2C9 poor metabolizers ）, the mean normalized steady-state sodium valproate concentrations were significantly higher in G3 （ 3.70 ± 0. 95 ） and G4 （ 4. 35 ± 1.48 ） patients when compared to those in G1 （2. 57 ±- 1.30, t = 3. 056,4. 490, both P 〈 0. 01 ） and G2 （2. 76 ± 1.19, t = 2. 827, 4. 462, both P 〈 0. 01 ） patients. The daily doses （rag/d） of sodium valproate received by G3 （ 19.46 ± 5.20 ） and G4 （19.30 ± 7.67） patients were significantly lower than that of G1 patients （24. 10 ± 6. 97, t = 2. 359, 2. 297, both P 〈 0. 05 ）. There were no differences in daily doses or normalized steady-state concentrations of sodium valproate among the CYP2A6＊ 4 or CYP2B6＊6 genotypic groups. Conclusions The CYP2C9 and CYP2C19 polvmorphisms have dramatic effects on the plasma concentration of sodium valproate. The daily doses of sodium valproate in G3 and G4 patients should be lower than usual.

关 键 词：癫痫 丙戊酸 血药浓度 芳基烃羟化酶类 氧化还原酶类 N-脱甲基 多态现象 遗传 

分 类 号：R135[医药卫生—劳动卫生]