Characterization of Nefazodone Time-dependent Inhibition of Cytochrome P450 3A

Nefazodone (Serzone®), marketed as an antidepressant, was discontinued in 2004 due to the rare incidence of hepatoxicity. In vitro studies focused on characterizing the metabolism and potential bioactivation pathways of nefazodone revealed that metabolism of nefazodone by CYP3A leads to the formation of multiple reactive metabolites that could contribute to nefazodone toxicity (Argoti et al., 2005; Kalgutkar et al., 2005; Bauman et al., 2008). The literature also reported nefazodone as a time-dependent inhibitor (TDI) of CYP3A4 (Kalgutkar et al., 2005; Bauman et al., 2008). However, the plausible mechanism of nefazodone-mediated inactivation of CYP3A4, particularly the role of reactive metabolites in CYP3A4 inactivation, remains unclear. In the work presented here, a comprehensive investigation of the CYP3A4- and CYP3A5-mediated metabolism of nefazodone was conducted to characterize the difference in metabolite formation, enzyme inhibition kinetics and conjugation of reactive metabolites towards metabolis...