UGT2B15 single nucleotide polymorphism reduces dabigatran acylglucuronide formation in humans.

Background: 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 UGT2B15 , has not been extensively explored in humans. This study aimed to investigate the effects of UGT2B15 , ABCB1 , and CES1 polymorphisms on the pharmacokinetics of DAB and its acylglucuronide metabolites in healthy subjects.
Methods: A total of 124 healthy males were genotyped for UGT2B15 , ABCB1 , and CES1 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.
Results: UGT2B15 c.253G>T significantly affected free DAB pharmacokinetics, with a lower T _max and oral clearance in TT genotype (n = 28, p < 0.05). For DABG, C _max 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 _all of DABG was highest in GG genotypes (327 ± 148.3 ng h·mL ^-1 ), followed by GT (238.7 ± 166.5 ng h·mL ^-1 ) and TT (223.3 ± 165.4 ng h·mL ^-1 ) genotypes ( p < 0.05). The metabolite-to-parent ratios (m/p ratios) for C _max and AUC _all were significantly higher in GG and GT genotypes than that in TT genotype. ABCB1 and CES1 polymorphisms had no significant impact on the pharmacokinetics of DAB or DABG.
Conclusion: UGT2B15 polymorphisms were associated with difference in DAB glucuronidation and pharmacokinetics in healthy male participants.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2025 Park, Kim, Bang, Kim, Yu and Park.)