【摘要】 抗癫痫药物治疗是控制癫痫的主要方法,但由于个体间对药物处置的差异性,患者对目前治疗的反应性并不一致。本研究通过在健康志愿者中进行的临床Ⅰ期剂量递增试验,考察了遗传和表观遗传变异是否影响抗癫痫药物氯桂丁胺（3,4-DCPB）的药代动力学表型。采用液相色谱-串联质谱（LC-MS/MS）法测定血浆中3,4-DCPB母药及其主要代谢物M1的浓度。通过基因分型和DNA甲基化水平分析细胞色素P450 2D6 （CYP2D6）、CYP2C9、CYP1A2、CYP2C19、CYP3A5、转运体ABCB1（C1236T）、核受体AhR、CAR和PXR的单核苷酸多态性（SNPs）。与野生型CYP2D6^*1/^*1纯合子（广泛代谢型,EMs）相比,变异等位基因CYP2D6^*10携带者（中间代谢型,IMs）中,代谢产物M1与3,4-DCPB母药的药时曲线下面积(AUC_0–t)的比值更低,血浆半衰期(t_1/2)更久,DNA甲基化水平更高。这些数据表明胞嘧啶的丢失（CYP2D6^*10,C>T）所诱导的表观基因突变可能解释3,4-DCPB基因型、表观基因型和药代动力学表型在个体差异之间的关系,为癫痫的个性化治疗提供新的思路。更多还原

【Abstract】 Antiepileptic drug therapy is a main method for controlling epilepsy,but the responses of patients to the current treatments are not consistent due to inter-individual differences in drug disposition.In the present study,we investigated whether genetic and epigenetic variants affected the pharmacokinetic phenotypes of the antiepileptic drug 3,4-dichlorophenyl-propenoyl-sec-butylamine（3,4-DCPB） in phase Ⅰ dose-escalation clinical trial in healthy subjects.The plasma concentrations of 3,4-DCPB and its major metabolite M1 were determinated by the liquid chromatography tandem mass spectrometry （LC-MS/MS） method.Single nucleotide polymorphisms （SNPs） of xenobiotic metabolisms including cytochrome P450 2D6 （CYP2D6）,CYP2C9,CYP1A2,CYP2C19,CYP3A5,transporter ABCB1 （C1236T）,nuclear receptors AhR,CAR and PXR were analyzed by genotyping and DNA methylation levels for these genes.Compared to the wild-type CYP2D6^*1/^*1 homozygote （extensive metabolizers,EMs）,the variant allelic CYP2D6^*10 carriers （intermediate metabolizers,IMs） showed that the area under the curve (AUC_0–t) ratios of metabolite M1/3,4-DCPB parent drug were lower,and the plasma half-life (t_1/2) ratios were prolonger,while the DNA methylation levels were higher.These data suggested that epimutation induced by lose （CYP2D6^*10,C>T） of cytosine,might explain the associations among genotype,epigenotype and individual differences in the pharmacokinetic phenotype of 3,4-DCPB,and provide new insight in personalized treatment of epilepsy.更多还原