异源物代谢的表观遗传学变异影响抗癫痫药3,4-DCPB药物代谢动力学表型个体差异

Epigenetic variants of xenobiotic metabolism affect individual differences in antiepileptic drug 3,4-DCPB pharmacokinetic phenotype

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P4502D6(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(AUC0–t)的比值更低,血浆半衰期(t1/2)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。

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 phaseⅠdose-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 P4502D6(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(AUC0–t)ratios of metabolite M1/3,4-DCPB parent drug were lower,and the plasma half-life(t1/2)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.