摘要
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 effects of UGTIA4 142T〉G polymorphism and blood concentration of valproic acid （VPA） on blood concentration of lamotrigine （LTG） in southem Chinese Han children with epilepsy, and to establish the prediction equation for quantitatively estimating blood concentration of LTG. METHODS： A total of 72 southern Chinese Han children with epilepsy selected from Guangzhou Women and Children＇s Medical Center during Jan. 2010-Sept. 2016 were given LTG＋VPA. LC-MS/MS and enzyme amplified immunoassay were adopted to determine the blood concentration of LTG and VPA. RFLP-PCR was adopted to determine UGTIA4 142T〉G polymorphism. The relationships of age, gender, blood concentration of VPA, UGTIA4 142T〉G polymorphism and LTG concentration-to-dose-ratio （CDR） were also investigate. The prediction equation for blood concentration of LTG was established by multiple linear regression analysis. RESULTS： Age and blood concentration of VPA were positively related to CDR of LTG （r=0.225, 0.300,P〈 0.05） ; there was no statistical significance in the influence of gender on CDR of LTG （P〉0.05）. UGT1A4 TT, TG and GG genotypes were detected in 39, 29, and 4 cases respectively; the frequencies of each genotype were in line with the Hardy-Weinberg balance （P〉0.05）. CDR of LTG of TT genotype was significantly lower than those of TG and GG genotype, with statistical significance （P〈0.05）. Results of multiple linear regression analysis showed that the dose of LTG （x1）, body weight （x2）, blood concentration of VPA （x3） and UGT1A4 142T〉G polymorphism （x4） were all related to blood concentration of LTG （P〈 0.05）. Using blood concentration of LTG （c） as dependent variable, above factors as independent variable, the regression equation was c= 0.794＋0.032x1- 0.057x2＋0.010x3＋0.532x4 （R4= 0.616, P〈 0.05 ; UGT1A4 TT genotype was equal to 0, TG and GG genotype was equal to 1）. There was a strong positive correlation between predicted blood concentration and measured ones （r=0.785, P= 0.001）. CONCLUSIONS： The dose of LTG, body weight, blood concentration of VPA and UGT1A4 142T〉G polymorphism may associated with blood concentration of LTG. Established prediction equation can provide reference for precise medication in southern Chinese Han children with epilepsy.
出处
《中国药房》
CAS
北大核心
2017年第20期2737-2742,共6页
China Pharmacy
基金
广东省科技计划项目(No.2009B060700016)
