ArticleDrug metabolism and disposition: the biological fate of chemicals2014
Identification of carboxylesterase-dependent dabigatran etexilate hydrolysis.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
39 citing papers in PubMed, 1 synthesis or guideline pooled it, 95 citations in OpenAlex.
- Association betweenFrontiers in cardiovascular medicine · 2022Pooled it
- The impact of CES1 genotypes on the pharmacokinetics of methylphenidate in healthy Danish subjects.British journal of clinical pharmacology · 2017Trial
- Effects of alcohol on human carboxylesterase drug metabolism.Clinical pharmacokinetics · 2015Trial
- Pharmacogenomics of direct oral anticoagulants: a systematic review and meta-analysis.Frontiers in cardiovascular medicine · 2026Review
- Idarucizumab more effectively reverses the anticoagulant effects of dabigatran acylglucuronide than dabigatran.Scientific reports · 2025Article
- Carboxylesterase Factors Influencing the Therapeutic Activity of Common Antiviral Medications Used for SARS-CoV-2 Infection.Pharmaceutics · 2025Review
- Evaluation of Drug-Drug Interactions Between Clarithromycin and Direct Oral Anticoagulants Using Physiologically Based Pharmacokinetic Models.Pharmaceutics · 2024Article
- Regulation of Human Hydrolases and Its Implications in Pharmacokinetics and Pharmacodynamics.Drug metabolism and disposition: the biological fate of chemicals · 2024Review
- Pleiotropic Effects of Direct Oral Anticoagulants in Chronic Heart Failure and Atrial Fibrillation: Machine Learning Analysis.Molecules (Basel, Switzerland) · 2024Article
- Kupffer-Cell-Targeted Carboxylesterase 1f Knockdown Deteriorates Lipopolysaccharide/D-Galactosamine-Induced Acute Liver Failure Through Regulating Cellular Polarization in Mice.Canadian journal of gastroenterology & hepatology · 2024Article
- Assessing the relative contribution of CYP3A-and P-gp-mediated pathways to the overall disposition and drug-drug interaction of dabigatran etexilate using a comprehensive mechanistic physiological-based pharmacokinetic model.Frontiers in pharmacology · 2024Article
- The History of mARC.Molecules (Basel, Switzerland) · 2023Review
- Physiologically-based pharmacokinetic modeling to predict drug-drug interactions of dabigatran etexilate and rivaroxaban in the Chinese older adults.European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences · 2023Article
- Personalizing Direct Oral Anticoagulant Therapy for a Diverse Population: Role of Race, Kidney Function, Drug Interactions, and Pharmacogenetics.Clinical pharmacology and therapeutics · 2023Review
- Effects of Simvastatin on Pharmacokinetics and Anticoagulant Effects of Dabigatran in Healthy Subjects.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Dabigatran Acylglucuronide, the Major Metabolite of Dabigatran, Shows a Weaker Anticoagulant Effect than Dabigatran.Pharmaceutics · 2022Article
- Physiologically-based pharmacokinetic modeling to evaluate in vitro-to-in vivo extrapolation for intestinal P-glycoprotein inhibition.CPT: pharmacometrics & systems pharmacology · 2022Article
- Novel Anthracycline Utorubicin for Cancer Therapy.Angewandte Chemie (International ed. in English) · 2021Article
- Novel Anthracycline Utorubicin for Cancer Therapy.Angewandte Chemie (Weinheim an der Bergstrasse, Germany) · 2021Article
- Bleeding complications in patients with gastrointestinal cancer and atrial fibrillation treated with oral anticoagulants.Cancer medicine · 2021Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Dabigatran etexilate (DABE) is an oral prodrug that is rapidly converted to the active thrombin inhibitor, dabigatran (DAB), by serine esterases. The aims of the present study were to investigate the in vitro kinetics and pathway of DABE hydrolysis by human carboxylesterase enzymes, and the effect of alcohol on these transformations. The kinetics of DABE hydrolysis in two human recombinant carboxylesterase enzymes (CES1 and CES2) and in human intestinal microsomes and human liver S9 fractions were determined. The effects of alcohol (a known CES1 inhibitor) on the formation of DABE metabolites in carboxylesterase enzymes and human liver S9 fractions were also examined. The inhibitory effect of bis(4-nitrophenyl) phosphate on the carboxylesterase-mediated metabolism of DABE and the effect of alcohol on the hydrolysis of a classic carboxylesterase substrate (cocaine) were studied to validate the in vitro model. The ethyl ester of DABE was hydrolyzed exclusively by CES1 to M1 (Km 24.9 ± 2.9 μM, Vmax 676 ± 26 pmol/min per milligram protein) and the carbamate ester of DABE was exclusively hydrolyzed by CES2 to M2 (Km 5.5 ± 0.8 μM; Vmax 71.1 ± 2.4 pmol/min per milligram protein). Sequential hydrolysis of DABE in human intestinal microsomes followed by hydrolysis in human liver S9 fractions resulted in complete conversion to DAB. These results suggest that after oral administration of DABE to humans, DABE is hydrolyzed by intestinal CES2 to the intermediate M2 metabolite followed by hydrolysis of M2 to DAB in the liver by CES1. Carboxylesterase-mediated hydrolysis of DABE was not inhibited by alcohol.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.