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

doi:10.5246/jcps.2023.01.001

中国药学(英文版) ›› 2023, Vol. 32 ›› Issue (1): 1-16.DOI: 10.5246/jcps.2023.01.001

• 【研究论文】 • 下一篇

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

逯颖媛¹^,³, 张梅², 尹胜菊¹, 董晓娜¹, 张志远¹, 程海旭¹, 屠鹏飞³, 窦桂芳⁴, 车永胜⁵, 徐争辉⁶, 徐枫⁷, 王宪⁷, 吕闯⁸, 楼雅卿¹, 章国良¹^,^*()

^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. 广州大学化学化工学院化学基础实验室, 广东广州 510006
^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) 024251

收稿日期:2022-10-16 修回日期:2022-11-12 接受日期:2022-11-26 出版日期:2023-01-31 发布日期:2023-01-31
通讯作者: 章国良
基金资助:
National Natural Science Foundation of China (Grants No. 81473276 and 81773809).

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

Yingyuan Lu¹^,³, Mei Zhang², Shengju Yin¹, Xiaona Dong¹, Zhiyuan Zhang¹, Haixu Cheng¹, Pengfei Tu³, Guifang Dou⁴, Yongsheng Che⁵, Zhenghui Xu⁶, Feng Xu⁷, Xian Wang⁷, Chuang Lu⁸, Yaqing Lou¹, Guoliang Zhang¹^,^*()

¹ Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
² Department of Pharmacy, Beijing Military Region General Hospital, Beijing 100700, China
³ State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
⁴ Laboratory of Pharmacokinetics, Beijing Institute of Radiation Medicine, Beijing 100850, China
⁵ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
⁶ CapitalBio Corporation, Beijing 102206, China
⁷ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
⁸ Department of Drug Metabolism & Pharmacokinetics (DMPK), Accent Therapeutics Incorporated, Massachusetts (MA), 024251, USA

Received:2022-10-16 Revised:2022-11-12 Accepted:2022-11-26 Online:2023-01-31 Published:2023-01-31
Contact: Guoliang Zhang

摘要/Abstract

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。

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

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.

Key words: Pharmacokinetics, Antiepileptic drug 3,4-DCPB, Individual difference, DNA methylation, CYP2D6*10 carriers, Epimutation, Phase I dose-escalation clinical trial

Supporting:

http://www.jcps.ac.cn/attached/file/20230202/20230202152240_308.pdf

逯颖媛, 张梅, 尹胜菊, 董晓娜, 张志远, 程海旭, 屠鹏飞, 窦桂芳, 车永胜, 徐争辉, 徐枫, 王宪, 吕闯, 楼雅卿, 章国良. 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[J]. 中国药学(英文版), 2023, 32(1): 1-16.

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. Epigenetic variants of xenobiotic metabolism affect individual differences in antiepileptic drug 3,4-DCPB pharmacokinetic phenotype[J]. Journal of Chinese Pharmaceutical Sciences, 2023, 32(1): 1-16.

图/表 7

Figure 1. Pharmacokinetics of 3,4-DCPB and its major metabolite M1 in phase 1 dose-escalation clinical trial in healthy subjects. (A) Chemical structures of 3,4-dichlorophenyl-propenoyl-sec-butylamine (3,4-DCPB) and (B) its major metabolite M1 (3,4-dichlorophenyl-propenoyl-sec-cyclohexane, 3,4-DCPC). (C) Plasma concentration-time curves of 3,4-DCPB and (D) metabolite M1 after the single three doses (100, 300, 900 mg) in thirty-six healthy Chinese subjects. (E) Plasma concentration-time curves of 3,4-DCPB and (F) metabolite M1 after the multiple three doses (100 mg bid, 200 mg bid, 200 mg tid, 7 d) in 33 healthy Chinese subjects.

Table 1. Pharmacokinetic parameters of (A) 3,4-dichlorophenyl-propenoyl-sec-butylamine (3,4-DCPB) parent drug and (B) its major metabolite M1 (3,4-dichlorophenyl-propenoyl-sec-cyclohexane, 3,4-DCPC) after the single oral administration of 3,4-DCPB tablet at three doses (100, 300, and 900 mg) in 36 healthy subjects (mean ± SD).

Table 2. Pharmacokinetic parameters of (A) 3,4-dichlorophenyl-propenoyl-sec-butylamine (3,4-DCPB) parent drug and (B) its major metabolite M1 (3,4-dichlorophenyl-propenoyl-sec-cyclohexane, 3,4-DCPC) after the multiple oral administration of 3,4-DCPB tablet at three doses (100 mg, bid; 200 mg, bid; 200 mg, tid, 7 d) in 33 healthy subjects (mean ± SD, n = 12 or n = 9 subjects).

Figure 2. Individual differences in 3,4-DCPB pharmacokinetics (PK). (A) Plasma half-life (t1/2) of 3,4-DCPB and metabolite M1 after the single three doses (n = 12 per dose group). (B) t1/2 of 3,4-DCPB and metabolite M1 after the multiple three doses (n = 12 or n = 9 per dose group). (C) Pharmacokinetic parameter ratios of metabolite M1/3,4-DCPB including the area under curve of the 3,4-DCPB plasma concentration (AUC0–t) values and (D) t1/2 values after single three doses or multiple three doses in phase 1 clinical trial in healthy volunteers. (E) Principal component analysis (PCA) for the individual differences of 3,4-DCPB pharmacokinetic parameters including the ratios of AUC0–t of M1/3,4-DCPB and the ratios of t1/2 of M1/3,4-DCPB in phase I dose-escalation clinical trial in healthy subjects.

Figure 3. Single nucleotide polymorphisms (SNPs) of 3,4-DCPB metabolizing genes and PK phenotype. (A) Allelic frequencies of 3,4-DCPB metabolic genes in cytochrome P450 enzymes (CYP2D6*10, CYP1A2*1F, CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP3A5*3), transporter (ABCB1), and nuclear receptors (AhR, CAR, PXR) in phase I dose-escalation clinical trial in Chinese subjects (n = 69 per genetic group). (B) Pharmacokinetics of 3,4-DCPB by CYP2D6*10, (C) CYP2C9*3, (D) CYP2C9*2, (E) CYP1A2, (F) AhR, (G) CYP2C19*2, (H) CYP2C19*3, (I) CYP3A5*3, (J) ABCB1 (1236 C > T), (K) CAR and (L) PXR genotyping as the wild-type homozygotes, variant heterozygotes, variant homozygotes, and variant allelic carriers (the sum of the variant heterozygote and variant homozygote genotypes).

Figure 4. Promotor region cytosine-guanine dinucleotide (CpG) sites methylation of 3,4-DCPB metabolizing genes. (A) Numbers of cytosine-guanine dinucleotide (CpG) sites in promotor and coding region of 3,4-DCPB metabolic genes. (B) Methylation levels of total CpG sites in promotor regions. (C) Methylation levels of single and average CpG sites in promotor regions of CYP2D6 gene. (D) Clustering heatmaps show average CpG sites in promotor region and (E) global genome. **P < 0.01, ##P < 0.01, compared with CYP2D6 gene promotor. (F) DNA methylation levels of global genome and 3,4-DCPB pharmacokinetics. AUC0–t ratios of metabolite M1/3,4-DCPB after single three doses. t1/2 ratios of metabolite M1/3,4-DCPB after single oral three doses. (G) AUC0–t ratios of metabolite M1/3,4-DCPB after multiple oral three doses. t1/2 ratios of metabolite M1/3,4-DCPB after multiple oral three doses. (H) DNA methylation levels of global genome on pharmacokinetics by CYP2D6 genotyping.

Figure 5. Putative causal variant relationship among genotype, epigenotype and 3.4-DCPB PK phenotype. (A) Chromosomic locations of 3,4-DCPB metabolic genes. (B) Genotyping for 3,4-DCPB metabolic genes including the wild-type homozygotes and the variant allelic carriers (the sum of the variant heterozygotes and variant homozygotes). (C) Area under curve (AUC0–t) ratio of M1/3,4-DCPB in plasma by genotyping. (D) Plasma half-life (t1/2) ratio of M1/3,4-DCPB by genotyping. (E) DNA methylation levels in global genome by genotyping. (F) Effects of epimutation induced by CYP2D6*10 (C > T, lose cytosine) on the 3,4-DCPB pharmacokinetics phenotypes in Chinese subjects. #P < 0.05, ∆P < 0.05, **P < 0.01, compared with the group of wild-type homozygotes genotype.

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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

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