Effects of UGT1A9 genetic polymorphisms on monohydroxylated derivative of oxcarbazepine concentrations and oxcarbazepine monotherapeutic efficacy in Chinese patients with epilepsy

The human UDP-glucuronosyltransferase which is genetically polymorphic catalyzes glucuronidations of various drugs. The interactions among UGT1A4, UGT1A6, UGT1A9, and UGT2B15 genetic polymorphisms, monohydroxylated derivative (MHD) of oxcarbazepine (OXC) plasma concentrations, and OXC monotherapeutic efficacy were explored in 124 Chinese patients with epilepsy receiving OXC monotherapy.MHD is the major active metabolite of OXC, and its plasma concentration was measured using high-performance liquid chromatography when patients reached their maintenance dose of OXC. Genomic DNA was extracted from whole blood and SNP genotyping performed using PCR followed by dideoxy chain termination sequencing. We followed the patients for at least 1 year to evaluate the OXC monotherapy efficacy. Patients were divided into two groups according to their therapeutic outcome: group 1, seizure free; group 2, not seizure free. The data were analyzed using T test, one-way analysis of variance (ANOVA), Kruskal-Wallis test, chi-square test, Fisher's exact test, correlation analysis, and multivariate regression analysis.T test analysis showed that MHD plasma concentrations were significantly different between the two groups (p = 0.002). One-way ANOVA followed by Bonferroni post hoc testing of four candidate SNPs revealed that carriers of the UGT1A9 variant allele I399 C > T (TT 13.28 +/- 7.44 mg/L, TC 16.41 +/- 6.53 mg/L) had significantly lower MHD plasma concentrations and poorer seizure control than noncarriers (CC 22.24 +/- 8.49 mg/L, p < 0.05).In our study, we have demonstrated the effects of UGT1A9 genetic polymorphisms on MHD plasma concentrations and OXC therapeutic efficacy. Through MHD monitoring, we can predict OXC therapeutic efficacy, which may be useful for the personalization of OXC therapy in epileptic patients.

人尿苷二磷酸葡萄糖醛酸转移酶具有基因多态性，可催化多种药物的葡萄糖醛酸化反应。本研究对124例接受奥卡西平（OXC）单药治疗的中国癫痫患者，探讨了UGT1A4、UGT1A6、UGT1A9和UGT2B15基因多态性、奥卡西平单羟基化衍生物（MHD）血浆浓度以及奥卡西平单药治疗疗效之间的相互关系。MHD是奥卡西平的主要活性代谢产物，当患者达到奥卡西平维持剂量时，采用高效液相色谱法测定其血浆浓度。从全血中提取基因组DNA，通过聚合酶链反应（PCR）结合双脱氧链终止测序进行单核苷酸多态性（SNP）基因分型。对患者随访至少1年以评估奥卡西平单药治疗疗效。根据治疗结果将患者分为两组：第1组，无发作；第2组，有发作。采用t检验、单因素方差分析（ANOVA）、Kruskal - Wallis检验、卡方检验、费舍尔精确检验、相关性分析和多元回归分析对数据进行分析。t检验分析显示两组之间MHD血浆浓度有显著差异（p = 0.002）。对4个候选SNP进行单因素方差分析及Bonferroni事后检验发现，UGT1A9变异等位基因I399 C>T的携带者（TT型13.28±7.44 mg/L，TC型16.41±6.53 mg/L）的MHD血浆浓度显著低于非携带者（CC型22.24±8.49 mg/L，p<0.05），且癫痫发作控制情况较差。在本研究中，我们证明了UGT1A9基因多态性对MHD血浆浓度和奥卡西平治疗疗效的影响。通过MHD监测，我们可以预测奥卡西平的治疗疗效，这可能对癫痫患者奥卡西平治疗的个体化有帮助。