Park Jin-Woo, Kim Jong-Min, Bang Young Yoon, Kim Kyoung-Ah, Yu Sungwook, Park Ji-Young
Department of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
Department of Neurology, Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
Front Pharmacol. 2025 Jan 9;15:1507915. doi: 10.3389/fphar.2024.1507915. eCollection 2024.
Dabigatran etexilate (DABE), a prodrug of dabigatran (DAB), is a direct thrombin inhibitor used to prevent ischemic stroke and thromboembolism during atrial fibrillation. The effect of genetic polymorphisms on its metabolism, particularly , has not been extensively explored in humans. This study aimed to investigate the effects of , , and polymorphisms on the pharmacokinetics of DAB and its acylglucuronide metabolites in healthy subjects.
A total of 124 healthy males were genotyped for , , and polymorphisms. After a single 150 mg dose of DABE, plasma concentrations of total and free DAB, as well as dabigatran acylglucuronide (DABG) were measured using LC-MS/MS. Pharmacokinetic parameters were analyzed using non-compartmental methods, and statistical comparisons were conducted between the genotype groups.
c.253G>T significantly affected free DAB pharmacokinetics, with a lower T and oral clearance in TT genotype (n = 28, < 0.05). For DABG, C was significantly higher in GG genotypes (n = 32, 42.3 ± 16.3 ng/mL) compared to that in GT (n = 64, 32.4 ± 20.5 ng/mL) and TT (29.7 ± 17.1 ng/mL) genotypes. Similarly, the AUC of DABG was highest in GG genotypes (327 ± 148.3 ng h·mL), followed by GT (238.7 ± 166.5 ng h·mL) and TT (223.3 ± 165.4 ng h·mL) genotypes ( < 0.05). The metabolite-to-parent ratios (m/p ratios) for C and AUC were significantly higher in GG and GT genotypes than that in TT genotype. and polymorphisms had no significant impact on the pharmacokinetics of DAB or DABG.
polymorphisms were associated with difference in DAB glucuronidation and pharmacokinetics in healthy male participants.
达比加群酯（DABE）是达比加群（DAB）的前体药物，是一种直接凝血酶抑制剂，用于预防心房颤动期间的缺血性中风和血栓栓塞。基因多态性对其代谢的影响，尤其是[具体基因多态性未提及]，在人类中尚未得到广泛研究。本研究旨在调查[具体基因多态性未提及]、[具体基因多态性未提及]和[具体基因多态性未提及]基因多态性对健康受试者中DAB及其酰基葡萄糖醛酸代谢物药代动力学的影响。
对总共124名健康男性进行了[具体基因多态性未提及]、[具体基因多态性未提及]和[具体基因多态性未提及]基因多态性的基因分型。单次服用150mg DABE后，使用液相色谱 - 串联质谱法测量总DAB和游离DAB以及达比加群酰基葡萄糖醛酸（DABG）的血浆浓度。使用非房室方法分析药代动力学参数，并在基因型组之间进行统计学比较。
c.253G>T显著影响游离DAB的药代动力学，TT基因型（n = 28，P<0.05）的T较低且口服清除率较低。对于DABG，GG基因型（n = 32，42.3±16.3ng/mL）的C显著高于GT基因型（n = 64，32.4±20.5ng/mL）和TT基因型（29.7±17.1ng/mL）。同样，DABG的AUC在GG基因型中最高（327±148.3ng·h·mL），其次是GT基因型（238.7±166.5ng·h·mL）和TT基因型（223.3±165.4ng·h·mL）（P<0.05）。GG和GT基因型中C和AUC的代谢物与母体比率（m/p比率）显著高于TT基因型。[具体基因多态性未提及]和[具体基因多态性未提及]基因多态性对DAB或DABG的药代动力学没有显著影响。
[具体基因多态性未提及]基因多态性与健康男性参与者中DAB葡萄糖醛酸化和药代动力学的差异有关。
