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Research ArticleArticle

Identification of Epoxide-Derived Metabolite(s) of Benzbromarone

Kai Wang, Hui Wang, Ying Peng and Jiang Zheng
Drug Metabolism and Disposition April 2016, 44 (4) 607-615; DOI: https://doi.org/10.1124/dmd.115.066803
Kai Wang
School of Pharmacy (K.W., H.W., Y.P.), Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education (J.Z.), Shenyang Pharmaceutical University, Shenyang, Liaoning, P. R. China; and Center for Developmental Therapeutics, Seattle Children’s Research Institute, Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington (J.Z.)
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Hui Wang
School of Pharmacy (K.W., H.W., Y.P.), Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education (J.Z.), Shenyang Pharmaceutical University, Shenyang, Liaoning, P. R. China; and Center for Developmental Therapeutics, Seattle Children’s Research Institute, Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington (J.Z.)
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Ying Peng
School of Pharmacy (K.W., H.W., Y.P.), Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education (J.Z.), Shenyang Pharmaceutical University, Shenyang, Liaoning, P. R. China; and Center for Developmental Therapeutics, Seattle Children’s Research Institute, Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington (J.Z.)
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Jiang Zheng
School of Pharmacy (K.W., H.W., Y.P.), Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education (J.Z.), Shenyang Pharmaceutical University, Shenyang, Liaoning, P. R. China; and Center for Developmental Therapeutics, Seattle Children’s Research Institute, Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington (J.Z.)
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Abstract

Benzbromarone (BBR) is a benzofuran derivative that has been quite useful for the treatment of gout; however, it was withdrawn from European markets in 2003 because of reported serious incidents of drug-induced liver injury. BBR-induced hepatotoxicity has been suggested to be associated with the formation of a quinone intermediate. The present study reported epoxide-derived intermediate(s) of BBR. An N-acetylcysteine (NAC) conjugate derived from epoxide metabolite(s) was detected in both microsomal incubations of BBR and urine samples of mice treated with BBR. The NAC conjugate was identified as 6-NAC BBR. Ketoconazole suppressed the bioactivation of BBR to the epoxide intermediate(s), and the CYP3A subfamily was the primary enzyme responsible for the formation of the epoxide(s). The present study provided new information on metabolic activation of BBR.

Footnotes

    • Received August 22, 2015.
    • Accepted January 13, 2016.
  • K.W. and H.W. contributed equally to this work.

  • This work was supported in part by the National Natural Science Foundation of China [Grants 81373471 and 81430086], and the Natural Science Foundation of Liaoning Province [Grant 2015020738].

  • dx.doi.org/10.1124/dmd.115.066803.

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

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (4)
Drug Metabolism and Disposition
Vol. 44, Issue 4
1 Apr 2016
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Research ArticleArticle

Epoxidation of Benzbromarone

Kai Wang, Hui Wang, Ying Peng and Jiang Zheng
Drug Metabolism and Disposition April 1, 2016, 44 (4) 607-615; DOI: https://doi.org/10.1124/dmd.115.066803

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Research ArticleArticle

Epoxidation of Benzbromarone

Kai Wang, Hui Wang, Ying Peng and Jiang Zheng
Drug Metabolism and Disposition April 1, 2016, 44 (4) 607-615; DOI: https://doi.org/10.1124/dmd.115.066803
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