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

作　　者：逯颖媛 张梅[2] 尹胜菊[1] 董晓娜 张志远 程海旭[1] 屠鹏飞[3] 窦桂芳[4] 车永胜 徐争辉 徐枫 王宪 吕闯 楼雅卿[1] 章国良[1] Yingyuan Lu;Mei Zhang;Shengju Yin;Xiaona Dong;Zhiyuan Zhang;Haixu Cheng;Pengfei Tu;Guifang Dou;Yongsheng Che;Zhenghui Xu;Feng Xu;Xian Wang;Chuang Lu;Yaqing Lou;Guoliang Zhang(Department of Pharmacology,School of Basic Medical Sciences,Peking University Health Science Center,Beijing 100191,China;Department of Pharmacy,Beijing Military Region General Hospital,Beijing 100700,China;State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University Health Science Center,Beijing 100191,China;Laboratory of Pharmacokinetics,Beijing Institute of Radiation Medicine,Beijing 100850,China;Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences,Beijing 100050,China;CapitalBio Corporation,Beijing 102206,China;Department of Physiology and Pathophysiology,School of Basic Medical Sciences,Peking University Health Science Center,Beijing 100191,China;Department of Drug Metabolism&Pharmacokinetics(DMPK),Accent Therapeutics Incorporated,Massachusetts(MA),024251,USA)

机构地区：[1]北京大学医学部基础医学院药理学系,北京100191 [2]北京军区总医院药剂科,北京100700 [3]北京大学医学部药学院天然药物及仿生药物国家重点实验室,北京100191 [4]军事医学科学院放射医学研究所药物代谢动力学研究室,北京100850 [5]中国医学科学院生物医学技术研究所,北京100050 [6]博奥晶典生物技术股份有限公司,北京102206 [7]北京大学医学部基础医学院生理与病理生理学系,北京100191 [8]美国阿克森特药物治疗股份有限公司药物代谢与药物代谢动力学(DMPK)实验室,美国马萨诸塞(MA)02425

出　　处：《Journal of Chinese Pharmaceutical Sciences》2023年第1期1-16,共16页中国药学（英文版）

基　　金：National Natural Science Foundation of China(Grants No.81473276 and 81773809)。

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.

关 键 词：药物代谢动力学 抗癫痫药氯桂丁胺 个体差异 DNA甲基化 CYP2D6*10携带者 表突变 临床Ⅰ期剂量递增试验 

分 类 号：R963[医药卫生—微生物与生化药学]