Evaluation of which reactive metabolite, if any, is responsible for a specific idiosyncratic reaction

Reactive metabolites are believed to be responsible for most idiosyncratic drug reactions. It is often assumed that if a reactive metabolite is found, it must be responsible for the idiosyncratic reactions associated with that drug. However, the evidence linking reactive metabolites and idiosyncratic reactions is circumstantial at best, and in many cases we have virtually no evidence. Furthermore, it is common for a drug to form several reactive metabolites, so it can be difficult to determine which, if any, is responsible for a given idiosyncratic reaction. Although the reactive metabolite hypothesis is logical, it has important implications for drug development, and we need to develop ways to test the hypothesis for specific drugs rigorously. Valid animal models are a powerful tool for testing whether a specific reactive metabolite is responsible for a specific adverse reaction and for studying further the mechanism by which it may induce such reactions; however, such models are rare.