Yang Xue, Yan Yuanliang, Fang Shu, Zeng Shuangshuang, Ma Hongying, Qian Long, Chen Xi, Wei Jie, Gong Zhicheng, Xu Zhijie
Department of Pharmacy.
Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders.
Medicine (Baltimore). 2019 Mar;98(12):e14908. doi: 10.1097/MD.0000000000014908.
Genetic polymorphisms are related to the concentration and efficacy of oxcarbazepine (OXC). 10-Hydroxycarbazepine (MHD) is the major pharmacologically active metabolite of OXC, and it exerts an antiepileptic effect. This study aimed to explore the connection between the MHD concentration and genes such as ATP-binding cassette B1 (ABCB1), ATP-binding cassette C2 (ABCC2), UDP-glucuronosyltransferase-2B7 and sodium voltage-gated channel alpha subunit 2 (SCN2A), which participate in the antiepileptic function of OXC.Total 218 Chinese epileptic patients, were stratified into different groups according to their age, body mass index (BMI) and OXC efficacy. The genotypes of 7 single nucleotide polymorphisms in all subjects were determined by polymerase chain reaction-improved multiple ligase detection reaction assay. The MHD plasma concentration was detected by high-performance liquid chromatography and then standardized through dosage and body weight.In general, the ABCC2 rs2273697 mutant (P = .026) required a significantly higher standardized MHD concentration. For age groups, carriers of the ABCC2 rs2273697 mutant showed a significantly higher standardized MHD concentration than noncarriers in the juvenile group (P = .033). In terms of BMI, a significantly higher standardized MHD concentration was found in the ABCB1 rs2032582 mutant of the normal weight group (P = .026). The SCN2A rs17183814 mutant required a significantly higher OXC maintenance (P = .014) in the low-weight group, while lower OXC maintenance dose (P = .044) and higher standardized MHD concentration (P = .007) in the overweight group.The ABCC2 rs2273697 polymorphism was significantly associated with MHD plasma concentration in the whole patient cohort and in patients stratified by different ages, this finding provides potential theoretical guidance for the rational and safe clinical use of OXC.
基因多态性与奥卡西平（OXC）的浓度及疗效相关。10-羟基奥卡西平（MHD）是OXC的主要药理活性代谢产物，具有抗癫痫作用。本研究旨在探讨MHD浓度与参与OXC抗癫痫功能的基因之间的联系，这些基因包括ATP结合盒转运体B1（ABCB1）、ATP结合盒转运体C2（ABCC2）、尿苷二磷酸葡萄糖醛酸基转移酶-2B7和钠电压门控通道α亚基2（SCN2A）。总共218例中国癫痫患者，根据年龄、体重指数（BMI）和OXC疗效被分层到不同组。通过聚合酶链反应-改良多重连接检测反应法测定所有受试者7个单核苷酸多态性的基因型。采用高效液相色谱法检测MHD血浆浓度，然后通过剂量和体重进行标准化。总体而言，ABCC2 rs2273697突变体（P = 0.026）需要显著更高的标准化MHD浓度。在年龄组中，ABCC2 rs2273697突变体携带者在青少年组中的标准化MHD浓度显著高于非携带者（P = 0.033）。就BMI而言，正常体重组中ABCB1 rs2032582突变体的标准化MHD浓度显著更高（P = 0.026）。低体重组中SCN2A rs17183814突变体需要显著更高的OXC维持剂量（P = 0.014），而超重组中OXC维持剂量较低（P = 0.044）且标准化MHD浓度较高（P = 0.007）。ABCC2 rs2273697多态性与整个患者队列以及按不同年龄分层的患者中的MHD血浆浓度显著相关，这一发现为OXC的合理安全临床应用提供了潜在的理论指导。
