Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor used against HIV-1. However, severe hepatotoxicity and adverse cutaneous effects raise concerns about its safety. NVP metabolism yields several phenolic compounds that could be involved in the toxic responses. To test this hypothesis, we investigated the ability of two phenolic NVP metabolites, 2-hydroxy-NVP and 3-hydroxy-NVP, to undergo oxidation and subsequent reaction with nucleophiles. The two metabolites were oxidized with a model chemical oxidant (Fr�my's salt) and also incubated with rat liver microsomes. We obtained evidence for the transient generation of the same quinone intermediate from the two phenols by both chemical and microsome-mediated oxidation. The quinone readily underwent hydrolytic conversion to a fully characterized ring-contraction product. In addition, multiple products were obtained by trapping with bionucleophiles (e.g. lysine, N-acetylcysteine, and ethyl valinate). These data support a possible role for phenolic oxidation in NVP-induced toxicitySupported by  FCT (PTDC/QUI-QUI/113910/2009; PEst-OE/QUI/UI0100/2011) and the NTP.

Oxidation of phenolic nevirapine metabolites to a reactive quinone – a plausible pathway to toxicity

244th National Meeting (2012)

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