Singularities of nevirapine metabolism: from sex-dependent differences to of idiosyncratic toxicity.

Nevirapine (NVP) is a 1st generation non-nucleoside reverse transcriptase inhibitor widely used for the treatment and prophylaxis of human immunodeficiency virus infection. The drug is taken throughout the patient´s life and, due to the availability of an extendend release formulation, it is administered once daily. This antiretroviral is one of the scarce examples of drugs with prescrition criteria based on sex, in order to prevent adverse reactions. The therapy with NVP has been associated with potentially life-threatening liver and idiosyncratic skin toxicity. Mutiple evidence has emerged regarding the formation of electrophilic NVP metabolites as crucial for adverse idiosyncratic reactions. The formation of reactive metabolites that yield covalent adducts with proteins has been demonstrated in patients under NVP-based treatment. Interestingly, several pharmacogenetic and sex-related factors associated to NVP toxicity can be mechanistically explained by an imbalance towards increased formation of NVP-derived reactive metabolites and/or impaired detoxification capability. Moreover, the haptenation of self-proteins by these reactive species provides a plausible link between NVP bioactivation and immunotoxicity, further supporting the relevance of this toxicokinetics hypothesis. In the current paper, we review the existing knowledge and recent developments on NVP metabolism and their relation to NVP toxicity.