Minimising the potential for metabolic activation in drug discovery

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Abstract
Investigations into the role of bioactivation in the pathogenesis of xenobiotic-induced toxicity have been a major area of research since the link between reactive metabolites and carcinogenesis was first reported in the 1930s. Circumstantial evidence suggests that bioactivation of relatively inert functional groups to reactive metabolites may contribute towards certain drug-induced adverse reactions. Reactive metabolites, if not detoxified, can covalently modify essential cellular targets. The identity of the susceptible biomacromolecule(s), and the physiological consequence of its covalent modification, will dictate the resulting toxicological response (e.g., covalent modification of DNA by reactive intermediates derived from procarcinogens that potentially leads to carcinogenesis). The formation of drug–protein adducts often carries a potential risk of clinical toxicities that may not be predicted from preclinical safety studies. Animal models used to reliably predict idiosyncratic drug toxicity are un...