Strategies for dealing with reactive intermediates in drug discovery and development.

Idiosyncratic drug reactions (IDRs; a specific type of drug toxicity characterized by delayed onset) are a major complication of drug therapy that need to be addressed during drug discovery and development. Efforts to improve drug safety are hampered by the lack of an accepted approach to predict IDRs, which in turn is due to the low incidence of occurrence of IDRs and the various potential mechanisms involved in these reactions. The concept of the relative rarity and formation of reactive metabolite of IDRs is briefly described. Hypothetical chemical mechanisms for the formation of reactive metabolites are summarized, including a classification of adverse drug reactions and types of reactive metabolites. The relative merits of current and potential strategies for dealing with reactive intermediates in drug discovery and development are examined, and the significance of covalent binding in drug discovery/development in vitro and in vivo systems is considered. Also discussed are the merits of tools (screening methods to trap reactive intermediates, enzyme inhibition and covalent binding) and strategies for predicting which new drugs have the potential to produce reactive intermediates and IDRs; these approaches may be considered to have the potential to improve the overall safety profile of drug candidates at various stages of the drug discovery and development process.