UGT2B15 single nucleotide polymorphism reduces dabigatran acylglucuronide formation in humans
BackgroundDabigatran 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 human...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1507915/full |
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| author | Jin-Woo Park Jin-Woo Park Jin-Woo Park Jong-Min Kim Young Yoon Bang Kyoung-Ah Kim Sungwook Yu Ji-Young Park |
| author_facet | Jin-Woo Park Jin-Woo Park Jin-Woo Park Jong-Min Kim Young Yoon Bang Kyoung-Ah Kim Sungwook Yu Ji-Young Park |
| author_sort | Jin-Woo Park |
| collection | DOAJ |
| description | BackgroundDabigatran 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.MethodsA 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.ResultsUGT2B15 c.253G>T significantly affected free DAB pharmacokinetics, with a lower Tmax and oral clearance in TT genotype (n = 28, p < 0.05). For DABG, Cmax 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 AUCall 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 Cmax and AUCall 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.ConclusionUGT2B15 polymorphisms were associated with difference in DAB glucuronidation and pharmacokinetics in healthy male participants. |
| format | Article |
| id | doaj-art-c05d1de92a9f4f7ea3663245215f39a3 |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-c05d1de92a9f4f7ea3663245215f39a32025-01-09T05:10:26ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-01-011510.3389/fphar.2024.15079151507915UGT2B15 single nucleotide polymorphism reduces dabigatran acylglucuronide formation in humansJin-Woo Park0Jin-Woo Park1Jin-Woo Park2Jong-Min Kim3Young Yoon Bang4Kyoung-Ah Kim5Sungwook Yu6Ji-Young Park7Department of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, Seoul, Republic of KoreaDepartment of Neurology, Anam Hospital, Korea University College of Medicine, Seoul, Republic of KoreaDivision of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United StatesDepartment of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, Seoul, Republic of KoreaDepartment of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, Seoul, Republic of KoreaDepartment of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, Seoul, Republic of KoreaDepartment of Neurology, Anam Hospital, Korea University College of Medicine, Seoul, Republic of KoreaDepartment of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, Seoul, Republic of KoreaBackgroundDabigatran 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.MethodsA 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.ResultsUGT2B15 c.253G>T significantly affected free DAB pharmacokinetics, with a lower Tmax and oral clearance in TT genotype (n = 28, p < 0.05). For DABG, Cmax 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 AUCall 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 Cmax and AUCall 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.ConclusionUGT2B15 polymorphisms were associated with difference in DAB glucuronidation and pharmacokinetics in healthy male participants.https://www.frontiersin.org/articles/10.3389/fphar.2024.1507915/fulldabigatranUGT2B15genetic polymorphismpharmacokineticsdabigatran acylglucuronide |
| spellingShingle | Jin-Woo Park Jin-Woo Park Jin-Woo Park Jong-Min Kim Young Yoon Bang Kyoung-Ah Kim Sungwook Yu Ji-Young Park UGT2B15 single nucleotide polymorphism reduces dabigatran acylglucuronide formation in humans Frontiers in Pharmacology dabigatran UGT2B15 genetic polymorphism pharmacokinetics dabigatran acylglucuronide |
| title | UGT2B15 single nucleotide polymorphism reduces dabigatran acylglucuronide formation in humans |
| title_full | UGT2B15 single nucleotide polymorphism reduces dabigatran acylglucuronide formation in humans |
| title_fullStr | UGT2B15 single nucleotide polymorphism reduces dabigatran acylglucuronide formation in humans |
| title_full_unstemmed | UGT2B15 single nucleotide polymorphism reduces dabigatran acylglucuronide formation in humans |
| title_short | UGT2B15 single nucleotide polymorphism reduces dabigatran acylglucuronide formation in humans |
| title_sort | ugt2b15 single nucleotide polymorphism reduces dabigatran acylglucuronide formation in humans |
| topic | dabigatran UGT2B15 genetic polymorphism pharmacokinetics dabigatran acylglucuronide |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1507915/full |
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