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Drug Metabolism & Disposition

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Research ArticleArticle

Identification of Carboxylesterase-Dependent Dabigatran Etexilate Hydrolysis

S. Casey Laizure, Robert B. Parker, Vanessa L. Herring and Zhe-Yi Hu
Drug Metabolism and Disposition February 2014, 42 (2) 201-206; DOI: https://doi.org/10.1124/dmd.113.054353
S. Casey Laizure
Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee
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Robert B. Parker
Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee
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Vanessa L. Herring
Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee
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Zhe-Yi Hu
Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee
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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.

Footnotes

    • Received August 20, 2013.
    • Accepted November 8, 2013.
  • This research was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant R15-GM096074].

  • dx.doi.org/10.1124/dmd.113.054353.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (2)
Drug Metabolism and Disposition
Vol. 42, Issue 2
1 Feb 2014
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Research ArticleArticle

Dabigatran Etexilate Hydrolysis

S. Casey Laizure, Robert B. Parker, Vanessa L. Herring and Zhe-Yi Hu
Drug Metabolism and Disposition February 1, 2014, 42 (2) 201-206; DOI: https://doi.org/10.1124/dmd.113.054353

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Research ArticleArticle

Dabigatran Etexilate Hydrolysis

S. Casey Laizure, Robert B. Parker, Vanessa L. Herring and Zhe-Yi Hu
Drug Metabolism and Disposition February 1, 2014, 42 (2) 201-206; DOI: https://doi.org/10.1124/dmd.113.054353
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