论文部分内容阅读
目的:探讨尿苷二磷酸葡糖醛酸转移酶(UGT)1A4 142T>G基因多态性和丙戊酸(VPA)血药浓度对我国南方汉族癫痫儿童体内拉莫三嗪(LTG)血药浓度的影响,并建立定量估算LTG血药浓度的预测方程。方法:选取2010年1月-2016年9月于广州市妇女儿童医疗中心就诊的南方汉族癫痫患儿72例,均采用LTG+VPA联合治疗。采用液相色谱-串联质谱法和酶放大免疫分析法分别测定患儿体内LTG和VPA的血药浓度,采用限制性片段长度多态性聚合酶链反应法测定其UGT1A4 142T>G多态性,并考察患儿年龄、性别、VPA血药浓度、UGT1A4 142T>G多态性与LTG标准化血药浓度(CDR)的相关性,并采用多重线性回归分析建立LTG血药浓度的预测方程。结果:患儿年龄、VPA血药浓度与LTG CDR呈正相关(r分别为0.225、0.300,P<0.05);性别对LTG CDR的影响无统计学意义(P>0.05)。共检出UGT1A4 TT、TG、GG基因型各39、29、4例,各基因型频率均符合HardyWeinberg平衡(P>0.05);TT基因型患儿LTG CDR显著低于TG、GG基因型,差异均有统计学意义(P<0.05)。多重线性回归分析结果显示,患儿LTG剂量(x_1)、体质量(x_2)、VPA血药浓度(x_3)、UGT1A4 142T>G多态性(x4)与LTG血药浓度有关(P<0.05);以LTG血药浓度为因变量(c),上述因素为自变量,得回归方程为c=0.794+0.032x_1-0.057x_2+0.010x_3+0.532x_4(R~2=0.616,P<0.05;其中,UGT1A4 TT基因型为0,TG、GG基因型为1),且LTG预测血药浓度和实测血药浓度的相关性良好(r=0.785,P=0.001)。结论:癫痫患儿的LTG剂量、体质量、VPA血药浓度、UGT1A4 142T>G多态性可能与LTG血药浓度有关;本研究建立的预测方程可为我国南方汉族癫痫患儿的精准用药提供参考。
Objective: To investigate the polymorphism of 1A4 142T> G gene of uridine diphosphate glucuronosyltransferase (UGT) and the plasma concentration of valproic acid (VPA) in Chinese children with seizures of Lamotrigine (LTG) Concentration, and establish a predictive equation for quantitative estimation of LTG plasma concentration. Methods: Seventy-two children with epilepsy in southern Han from January 2010 to September 2016 in Guangzhou Women and Children’s Medical Center were enrolled in this study. All of them were treated with combination of LTG and VPA. Plasma concentrations of LTG and VPA in children were measured by liquid chromatography-tandem mass spectrometry and enzyme-immunoassay, UGT1A4 142T> G polymorphism was determined by restriction fragment length polymorphism polymerase chain reaction (PCR-RFLP) The correlation between age, gender, VPA plasma concentration, UGT1A4 142T> G polymorphism and LTG normalized plasma concentration (CDR) was examined. Multiple linear regression analysis was used to establish the predictive equation of LTG plasma concentration. Results: There was a positive correlation between age and VPA concentration and LTG CDR (r = 0.225,0.300, P <0.05). There was no significant difference in gender and LTG CDR (P> 0.05). A total of 39, 29, and 4 cases of genotypes of UGT1A4 TT, TG and GG were detected, and the genotype frequencies of each genotype were in accordance with HardyWeinberg equilibrium (P> 0.05). LTG CDRs in TT genotype children were significantly lower than those in TG and GG genotypes All were statistically significant (P <0.05). Multiple linear regression analysis showed that LTG dose (x_1), body weight (x_2), VPA blood concentration (x_3) and UGT1A4 142T> G polymorphism (x4) were related to LTG plasma concentration (P <0.05) ; The concentration of LTG as the dependent variable (c), the above factors as independent variables, the regression equation was c = 0.794 + 0.032x_1-0.057x_2 + 0.010x_3 + 0.532x_4 (R ~ 2 = 0.616, P <0.05; , UGT1A4 TT genotype was 0, TG, GG genotype was 1), and the correlation between LTG predicted plasma concentration and measured plasma concentration was good (r = 0.785, P = 0.001). Conclusion: LTG dose, body weight, VPA plasma concentration, UGT1A4 142T> G polymorphism in children with epilepsy may be related to LTG plasma concentration. The prediction equation established in this study may provide a reference for the precise medication in children with epilepsy in South China .