In vitro analysis of idiosyncratic drug reactions

Adverse drug reactions unrelated to dose or blood level remain a major diagnostic problem, source of morbidity or even mortality for patients, and threat to the development of new therapeutic agents. Many such reactions are mediated by electrophilic drug metabolites capable of covalently interacting with cell macromolecules. Such interactions can result in cell death, mutations, or formation of haptens. We have used human cells as targets of metabolites generated by murine hepatic microsomes as a means of diagnosing reactions (in vitro re-challenge), studying their pharmacogenetic basis, and predicting toxicity risk from future treatment. Such an approach has been particularly useful in studying toxic reactions to liver and bone marrow caused by aromatic anticonvulsants such as phenytoin.