Animal models of idiosyncratic drug reactions.

Idiosyncratic drug reactions represent a major problem. In most cases the mechanisms of these reactions are unknown, but circumstantial evidence points to the involvement of reactive metabolites and the characteristics of the reactions suggest involvement of the immune system. If progress is to be made in dealing with these adverse reactions it is essential that we have a better understanding of their mechanisms, and it is hard to imagine testing mechanistic hypotheses without good animal models. Unfortunately, idiosyncratic reactions are also idiosyncratic in animals so few good models exist. The best models, in which a rodent develops a clinical syndrome similar to that which occurs in humans, appear to be penicillamine-induced autoimmunity in Brown Norway rats and nevirapine-induced skin rash in rats. Sulfamethoxazole-induced hypersensitivity in dogs and propylthiouracil-induced autoimmunity in cats are also similar to adverse reactions that occur in people, but they have practical limitations. Halothane-induced liver toxicity in guinea pigs and amodiaquine-induced bone marrow and liver toxicity in rats represent models in which there is an immune response and mild, reversible toxicity. It is possible that the development of immune tolerance is what limits the toxicity in these models, and if this is true, interventions that prevent tolerance might lead to good models. Although the history of developing animal models of idiosyncratic drug reactions is mostly one of failure, such models are essential. A better understanding of immune tolerance may greatly facilitate the development of better models; transgenic technology may also provide an important tool.