CYP2C9 and 3A4 play opposing roles in bioactivation and detoxification of diphenylamine NSAIDs.

Diphenylamine NSAIDs are taken frequently for chronic pain conditions, yet their use may potentiate hepatotoxicity risks through poorly characterized metabolic mechanisms. Our previous work revealed that seven marketed or withdrawn diphenylamine NSAIDs undergo bioactivation into quinone-species metabolites, whose reaction specificities depended on halogenation and the type of acidic group on the diphenylamine. Herein, we identified cytochromes P450 responsible for those bioactivations, determined reaction specificities, and estimated relative contributions of enzymes to overall hepatic bioactivations and detoxifications.