Nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor used against HIV-1, is associated with liver and skin toxicities. NVP metabolism to 4-hydroxymethyl-NVP (12-OH-NVP) is thought to play a role in these processes but other pathways could be involved. 12-OH-NVP undergoes further metabolism to 4-carboxy-NVP via the aldehyde, 4-formyl-NVP.  This species may bind to biomacromolecules but has so far eluded detection.  To investigate this pathway, we  incubated NVP and 12-OH-NVP with rat and human liver microsomes and rat liver cytosol. In all instances, LC-ESI-MS confirmed the formation of 4-formyl-NVP, trapped as a hydrazone derivative.  Incubation of 4-formyl-NVP with Human serum albumin, followed by reduction and enzymatic hydrolysis, yielded a lysine adduct, identified by LC-ESI-MS through comparison with a synthetic standard. Likewise, incubation of 4-formyl-NVP with Human hemoglobin yielded an adduct  with the N-terminal valine, characterized upon reduction and N-alkyl-Edman degradation. These results suggest that 4-formyl-NVP could play a role in NVP-induced toxicity.

Nevirapine metabolism to 4-formyl-nevirapine: Possible role in nevirapine toxicity

242nd National Meeting (2011)

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