Future of toxicology-metabolic activation and drug design: Challenges and opportunities in chemical toxicology

The issue of chemically reactive drug metabolites is one of growing concern in the pharmaceutical industry inasmuch as some, but not all, reactive intermediates are believed to play a role as mediators of drug-induced toxicities. While it is now relatively straightforward to identify these short-lived electrophilic species through appropriate in vitro "trapping" experiments, our current understanding of mechanistic aspects of xenobiotic-induced toxicities is such that we cannot predict which reactive intermediates are likely to cause a toxic insult and which will be benign. Little is known about the identities of the macromolecular targets (primarily proteins) of these electrophiles or the functional consequences of their covalent modification by reactive drug metabolites. As a result, several companies have adopted approaches to minimize the potential for metabolic activation of drug candidates at the discovery/lead optimization phase as a default strategy. However, research leading to a deeper insight into mechanistic aspects of toxicities caused by reactive drug metabolites will aid greatly in the rational design of drug candidates with superior safety profiles and represents a challenging and exciting opportunity for chemical toxicology.