Drugs can be converted to chemically reactive metabolites by drug metabolizing enzymes.  Developing the link between generation of chemically reactive metabolites and toxicity is challenging.  Retrospective analysis of instances of drug toxicity wherein the toxicity can be associated with reactive metabolites has been done for many examples, however to use reactive metabolite data in a prospective manner to predict which drugs may cause toxicity is extremely challenging.  In drug research, in vitro drug metabolism assays such as the generation of nucleophile adducts of reactive metabolites in drug metabolism incubations or measurement of covalent binding to macromolecules in vitro have been used as measures of bioactivation and warning signs for potential toxicity.  We and others have attempted to categorize drugs based on a combination of covalent binding rate in vitro and in vivo daily dose.  This concept has been extended to the characterization of drugs that already have reactive electrophilic substituents (without metabolic activation).  An �avoidance� strategy used in early drug design, based on structural alerts and in vitro drug metabolism data will be described.  Until better knowledge becomes available that shows a quantitative and mechanistic cause-and-effect between covalent binding and toxicity, this will continue to be a daunting challenge to those engaged in the discovery and development of new medicines.

Metabolic activation and reactive metabolites

248th National Meeting (2014)

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