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Research ArticleArticle

Arylacetamide Deacetylase is Responsible for Activation of Prasugrel in Human and Dog

Takaya Kurokawa, Tatsuki Fukami, Tomohiro Yoshida and Miki Nakajima
Drug Metabolism and Disposition March 2016, 44 (3) 409-416; DOI: https://doi.org/10.1124/dmd.115.068221
Takaya Kurokawa
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan
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Tatsuki Fukami
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan
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Tomohiro Yoshida
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan
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Miki Nakajima
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan
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Abstract

Prasugrel, a thienopyridine anti-platelet agent, is pharmacologically activated by hydrolysis and hydroxylation. It is efficiently hydrolyzed in the intestine after oral administration, and the enzyme responsible for the hydrolysis in humans was demonstrated to be carboxylesterase (CES)2. Prasugrel hydrolase activity is detected in dog intestines, where CES enzymes are absent; therefore, this prompted us to investigate the involvement of an enzyme(s) other than CES. Human arylacetamide deacetylase (AADAC) is highly expressed in the small intestine, catalyzing the hydrolysis of several clinical drugs containing small acyl moieties. In the present study, we investigated whether AADAC catalyzes prasugrel hydrolysis. Recombinant human AADAC was shown to catalyze prasugrel hydrolysis with a CLint value of 50.0 ± 1.2 ml/min/mg protein with a similar Km value to human intestinal and liver microsomes, whereas the CLint values of human CES1 and CES2 were 4.6 ± 0.1 and 6.6 ± 0.3 ml/min/mg protein, respectively. Inhibition studies using various chemical inhibitors and the relative activity factor approach suggested that the contribution of AADAC to prasugrel hydrolysis in human intestine is comparable to that of CES2. In dog intestine, the expression of AADAC, but not CES1 and CES2, was confirmed by measuring the marker hydrolase activities of each human esterase. The similar Km values and inhibition profiles between recombinant dog AADAC and small intestinal microsomes suggest that AADAC is a major enzyme responsible for prasugrel hydrolysis in dog intestine. Collectively, we found that AADAC largely contributes to prasugrel hydrolysis in both human and dog intestine.

Footnotes

    • Received November 4, 2015.
    • Accepted December 29, 2015.
  • This work was supported in part by a Grant-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Science [Grant 26860098].

  • dx.doi.org/10.1124/dmd.115.068221.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (3)
Drug Metabolism and Disposition
Vol. 44, Issue 3
1 Mar 2016
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Research ArticleArticle

Prasugrel Hydrolysis by AADAC in Human and Dog

Takaya Kurokawa, Tatsuki Fukami, Tomohiro Yoshida and Miki Nakajima
Drug Metabolism and Disposition March 1, 2016, 44 (3) 409-416; DOI: https://doi.org/10.1124/dmd.115.068221

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Research ArticleArticle

Prasugrel Hydrolysis by AADAC in Human and Dog

Takaya Kurokawa, Tatsuki Fukami, Tomohiro Yoshida and Miki Nakajima
Drug Metabolism and Disposition March 1, 2016, 44 (3) 409-416; DOI: https://doi.org/10.1124/dmd.115.068221
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