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

doi:10.5246/jcps.2023.01.001

Abstract

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

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.

Figures/Tables 7

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).

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