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Benzbromarone (BBR) is a benzofuran derivative that has been quite useful for the treatment of gout; however, it was withdrawn from European markets in 2003 because of reported serious incidents of drug-induced liver injury.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].
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- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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