ABSTRACT
The biotransformation of relatively innocuous chemicals to electrophilic reactive metabolites (RMs), commonly referred to as bioactivation, is viewed as an unfavorable feature in drug candidates given the propensity of RMs to covalently modify of DNA resulting in genotoxicity (Dobo et al., 2009) and/or inactivate cytochrome P450 (CYP) isoform(s) leading to clinical drug-drug interactions (DDIs) (Orr et al., 2012). In addition, it is now widely accepted that the generation of an RM is an obligatory step in the pathogenesis of some idiosyncratic adverse drug reactions (IADRs) (Guengerich and MacDonald, 2007; Li and Uetrecht, 2010; Uetrecht, 2008). IADRs can manifest as rare and sometimes life-threatening reactions (e.g., drug-induced liver injury [DILI], skin rashes, and blood dyscracias) in drug-treated patients that cannot be explained by the primary pharmacology of the drug. For instance, nefazodone is used to treat depression but can cause DILI (Kalgutkar et al., 2005a). Many IADRs are immune mediated and occur in very low frequency (1 in 10,000 or 1 in 100,000) in a small subset of patients either acutely or as a delayed response. IADRs, by definition, are difficult to reproduce in the human population and there are few, if any, generally applicable animal models for examining these toxicities in preclinical discovery/development (Uetrecht, 2006). Consequently, these reactions are often not detected until the drug has gained broad exposure in a large patient population. Amongst all IADRs, DILI remains a leading cause of acute hepatic failure and a major reason for withdrawal of marketed therapeutic agents (Leise et al., 2014).
