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Research ArticleArticle

Role of Human Arylacetamide Deacetylase (AADAC) on Hydrolysis of Eslicarbazepine Acetate and Effects of AADAC Genetic Polymorphisms on Hydrolase Activity

Keiya Hirosawa, Tatsuki Fukami, Kiyomichi Tashiro, Yoshiyuki Sakai, Fumiya Kisui, Masataka Nakano and Miki Nakajima
Drug Metabolism and Disposition April 2021, 49 (4) 322-329; DOI: https://doi.org/10.1124/dmd.120.000295
Keiya Hirosawa
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan (K.H., T.F., K.T., Y.S., F.K., Ma.N., Mi.N.); and WPI Nano Life Science Institute, Kakuma-machi, Kanazawa, Japan (T.F., Ma.N., Mi.N.)
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Tatsuki Fukami
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan (K.H., T.F., K.T., Y.S., F.K., Ma.N., Mi.N.); and WPI Nano Life Science Institute, Kakuma-machi, Kanazawa, Japan (T.F., Ma.N., Mi.N.)
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Kiyomichi Tashiro
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan (K.H., T.F., K.T., Y.S., F.K., Ma.N., Mi.N.); and WPI Nano Life Science Institute, Kakuma-machi, Kanazawa, Japan (T.F., Ma.N., Mi.N.)
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Yoshiyuki Sakai
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan (K.H., T.F., K.T., Y.S., F.K., Ma.N., Mi.N.); and WPI Nano Life Science Institute, Kakuma-machi, Kanazawa, Japan (T.F., Ma.N., Mi.N.)
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Fumiya Kisui
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan (K.H., T.F., K.T., Y.S., F.K., Ma.N., Mi.N.); and WPI Nano Life Science Institute, Kakuma-machi, Kanazawa, Japan (T.F., Ma.N., Mi.N.)
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Masataka Nakano
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan (K.H., T.F., K.T., Y.S., F.K., Ma.N., Mi.N.); and WPI Nano Life Science Institute, Kakuma-machi, Kanazawa, Japan (T.F., Ma.N., Mi.N.)
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Miki Nakajima
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan (K.H., T.F., K.T., Y.S., F.K., Ma.N., Mi.N.); and WPI Nano Life Science Institute, Kakuma-machi, Kanazawa, Japan (T.F., Ma.N., Mi.N.)
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Abstract

Human arylacetamide deacetylase (AADAC) plays a role in the detoxification or activation of drugs and is sometimes involved in the incidence of toxicity by catalyzing hydrolysis reactions. AADAC prefers compounds with relatively small acyl groups, such as acetyl groups. Eslicarbazepine acetate, an antiepileptic drug, is a prodrug rapidly hydrolyzed to eslicarbazepine. We sought to clarify whether AADAC might be responsible for the hydrolysis of eslicarbazepine acetate. Eslicarbazepine acetate was efficiently hydrolyzed by human intestinal and liver microsomes and recombinant human AADAC. The hydrolase activities in human intestinal and liver microsomes were inhibited by epigallocatechin gallate, a specific inhibitor of AADAC, by 82% and 88% of the control, respectively. The hydrolase activities in liver microsomes from 25 human livers were significantly correlated (r = 0.87, P < 0.001) with AADAC protein levels, suggesting that the enzyme AADAC is responsible for the hydrolysis of eslicarbazepine acetate. The effects of genetic polymorphisms of AADAC on eslicarbazepine acetate hydrolysis were examined by using the constructed recombinant AADAC variants with T74A, V172I, R248S, V281I, N366K, or X400Q. AADAC variants with R248S or X400Q showed lower activity than wild type (5% or 21%, respectively), whereas those with V172I showed higher activity than wild type (174%). Similar tendencies were observed in the other four substrates of AADAC; that is, p-nitrophenyl acetate, ketoconazole, phenacetin, and rifampicin. Collectively, we found that eslicarbazepine acetate is specifically and efficiently hydrolyzed by human AADAC, and several AADAC polymorphic alleles would be a factor affecting the enzyme activity and drug response.

SIGNIFICANCE STATEMENT This is the first study to clarify that arylacetamide deacetylase (AADAC) is responsible for the activation of eslicarbazepine acetate, an antiepileptic prodrug, to eslicarbazepine, an active form, in the human liver and intestines. In addition, we found that several AADAC polymorphic alleles would be a factor affecting the enzyme activity and drug response.

Footnotes

    • Received October 24, 2020.
    • Accepted January 7, 2021.
  • This work was supported in part by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science [19K07082].

  • https://doi.org/10.1124/dmd.120.000295.

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

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 49 (4)
Drug Metabolism and Disposition
Vol. 49, Issue 4
1 Apr 2021
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Research ArticleArticle

Role of AADAC on Eslicarbazepine Acetate Hydrolysis

Keiya Hirosawa, Tatsuki Fukami, Kiyomichi Tashiro, Yoshiyuki Sakai, Fumiya Kisui, Masataka Nakano and Miki Nakajima
Drug Metabolism and Disposition April 1, 2021, 49 (4) 322-329; DOI: https://doi.org/10.1124/dmd.120.000295

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Research ArticleArticle

Role of AADAC on Eslicarbazepine Acetate Hydrolysis

Keiya Hirosawa, Tatsuki Fukami, Kiyomichi Tashiro, Yoshiyuki Sakai, Fumiya Kisui, Masataka Nakano and Miki Nakajima
Drug Metabolism and Disposition April 1, 2021, 49 (4) 322-329; DOI: https://doi.org/10.1124/dmd.120.000295
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