Development and validation of LC–MS/MS method for simultaneous determination of dabigatran etexilate and its active metabolites in human plasma, and its application in a pharmacokinetic study

Park, In-Hwan; Park, Jin-Woo; Chung, Hyewon; Kim, Jong Min; Lee, Sang-Jin; Kim, Kyoung Ah; Park, Jiyoung

doi:10.1016/j.jpba.2021.114220

Cited by 6 publications

(4 citation statements)

References 15 publications

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“…As previous reported, dabigatran is mainly eliminated in a non-metabolized form by urine (80%), and approximately 20% is conjugated to form dabigatran acylglucuronide eliminated in stools (Blech et al, 2008). While recent research by Park et al (2021) with a new direct measurement method revealed that the portion of dabigatran conjugated to form dabigatran acylglucuronide would be much higher than previous results by the old indirect method. As renal excretion is the predominant elimination pathway for dabigatran, the medication is avoided in patients with impaired kidney function-especially those with end-stage renal disease (Ašić et al, 2018).…”

Section: Discussionmentioning

confidence: 72%

SLC4A4, FRAS1, and SULT1A1 Genetic Variations Associated With Dabigatran Metabolism in a Healthy Chinese Population

Xie

Liu

et al. 2022

Front. Genet.

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Background: The purpose of this study was to identify genetic variations associated with the metabolism of dabigatran in healthy Chinese subjects, with particular focus given to pharmacokinetics (PK) and pharmacodynamics (PD).Methods: Healthy Chinese adults aged 18–65 years with unknown genotypes from a bioequivalence trial were included according to the protocol registered at ClinicalTrial.org (NCT03161496). All subjects received a single dose (150 mg) of dabigatran etexilate. PK (main outcomes: area under the concentration-time, AUC0-t, of total and free dabigatran) and PD (main outcomes: anti-FIIa activity, APTT, and PT) parameters were evaluated. Whole-exome sequencing and genome-wide association analyses were performed. Additionally, candidate gene association analyses related to dabigatran were conducted.Results: A total of 118 healthy Chinese subjects were enrolled in this study. According to the p-value suggestive threshold (1.0 × 10−4), the following three SNPs were found to be associated with the AUC0–t of total dabigatran: SLC4A4 SNP rs138389345 (p = 5.99 × 10−5), FRAS1 SNP rs6835769 (p = 6.88 × 10−5), and SULT1A1 SNP rs9282862 (p = 7.44 × 10−5). Furthermore, these SNPs were also found to have significant influences on the AUC0–t of free dabigatran, maximum plasma concentration, and anti-FIIa activity (p < 0.05). Moreover, we identified 30 new potential SNPs of 13 reported candidate genes (ABCB1, ABCC2, ABCG2, CYP2B6, CYP1A2, CYP2C19, CYP3A5, CES1, SLCO1B1, SLC22A1, UGT1A1, UGT1A9, and UGT2B7) that were associated with drug metabolism.Conclusion: Genetic variations were indeed found to impact dabigatran metabolism in a population of healthy Chinese subjects. Further research is needed to explore the more detailed functions of these SNPs. Additionally, our results should be verified in studies that use larger sample sizes and investigate other ethnicities.

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Section: Discussionmentioning

confidence: 72%

SLC4A4, FRAS1, and SULT1A1 Genetic Variations Associated With Dabigatran Metabolism in a Healthy Chinese Population

Xie

Liu

et al. 2022

Front. Genet.

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“…Separate plasma samples were kept frozen below −70 ℃ until analysis. Plasma concentrations of dabigatran etexilate, dabigatran, and dabigatran acylglucuronide were quantified using a high-performance liquid chromatography (Nanospace series SI-2, Shiseido Co., Ltd., Tokyo, Japan) coupled with tandem mass spectrometry (API4000, AB SCIEX LLC, Framingham, MA, USA) method [ 33 ]. The method was validated in terms of selectivity, linearity, precision, accuracy, recovery, matrix effect, and stability prior to the analysis.…”

Section: Methodsmentioning

confidence: 99%

Effects of Simvastatin on Pharmacokinetics and Anticoagulant Effects of Dabigatran in Healthy Subjects

et al. 2023

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Higher risk of major hemorrhage associated with concomitant use of dabigatran and simvastatin compared to other statins was previously reported with a suggestion of P-glycoprotein-mediated interaction. The aim of this study was to evaluate the effects of simvastatin on pharmacokinetics and anticoagulant effects of dabigatran, a direct oral anticoagulant. A total of 12 healthy subjects were enrolled in an open-label, two-period, single sequence study. Subjects were given 150 mg of dabigatran etexilate followed by 40 mg of once-daily simvastatin for seven days. Dabigatran etexilate was administered with simvastatin on the seventh day of simvastatin administration. Blood samples for pharmacokinetic and pharmacodynamic analyses were obtained until 24 h post-dose of dabigatran etexilate with or without co-administration of simvastatin. Pharmacokinetic parameters were derived from noncompartmental analysis for dabigatran etexilate, dabigatran, and dabigatran acylglucuronide. When simvastatin was co-administered, geometric mean ratios of area under time-concentration curves for dabigatran etexilate, dabigatran, and dabigatran acylglucuronide were 1.47, 1.21, and 1.57, respectively, compared to when dabigatran etexilate was administered alone. Thrombin generation assay and coagulation assay showed similar profiles between before and after co-administration of simvastatin. This study provides evidence that simvastatin treatment plays a minor role in modulating pharmacokinetics and anticoagulant effects of dabigatran etexilate.

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“…Dabigatran has the chemical name of N- [[2-[[[4-(aminoiminomethyl) phenyl] amino] methyl]-1-methly-1H-benzymidazole-5-yl] carbonyl]-N-2-pyridinyl β-alanine. Dabigatran has poor oral bioavailability (6-7%) due to its high polarity, so its prodrug is widely used, namely dabigatran etexilate, which is easily absorbed in the digestive system [27]. The log P of dabigatran is 2.17, while dabigatran etexilate has a log P of 5.17.…”

Section: Oral Anticoagulant Non-vitamin K Antagonistmentioning

confidence: 99%

A Deep Overview of Anticoagulant Drugs: Recent Synthesis and Their Activity Assay

Astuti,

Ibrahim,

Zulfikar

et al. 2024

Indones. J. Chem.

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During the unprecedented COVID-19 pandemic, anticoagulant drugs have emerged as a crucial component of treatment alongside antivirus medications. Patients with severe COVID-19 frequently have critical conditions marked by blood clot development, necessitating the administration of anticoagulants. This review aims to provide a comprehensive overview of various anticoagulant drugs, their synthesis methods, and assays employed to predict their anticoagulant activity. Notable anticoagulant categories frequently utilized include oral anticoagulants heparin, non-vitamin K antagonists, and vitamin K antagonists. In recent years, the development of new anticoagulants has seen a shift towards a multifaceted approach that combines in silico prediction with in vitro and in vivo assays. In silico prediction techniques play a pivotal role in the initial screening process. This integrated approach has yielded promising results, paving the way for the synthesis of novel anticoagulant candidates, as substantiated by a battery of in vitro, in vivo, and ex-vivo tests.

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Development and validation of LC–MS/MS method for simultaneous determination of dabigatran etexilate and its active metabolites in human plasma, and its application in a pharmacokinetic study

Cited by 6 publications

References 15 publications

SLC4A4, FRAS1, and SULT1A1 Genetic Variations Associated With Dabigatran Metabolism in a Healthy Chinese Population

SLC4A4, FRAS1, and SULT1A1 Genetic Variations Associated With Dabigatran Metabolism in a Healthy Chinese Population

Effects of Simvastatin on Pharmacokinetics and Anticoagulant Effects of Dabigatran in Healthy Subjects

A Deep Overview of Anticoagulant Drugs: Recent Synthesis and Their Activity Assay

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