Jack P. Uetrecht

Idiosyncratic drug reactions are those which do not involve any of the known pharmacological effects of a drug and do not occur in most humans or animals at any dose of the drug. These reactions are often life-threatening and at present are impossible to predict. Although idiosyncratic reactions often have characteristics that suggest an immune reaction, in most cases involvement of the immune system has not been demonstrated and the mechanism is unknown. In general it is believed that a drug must covalently bind to protein in order to initiate an immune reaction. Most drugs are not sufficiently reactive to bind to protein and must be metabolized to a reactive metabolite in order to bind to protein and induce an adverse reaction. Most drug metabolism occurs in the liver, and although many idiosyncratic drug reactions involve the liver, many involve other organs, especially the skin and bone marrow. In view of their reactive nature most reactive metabolites probably must be formed in the organ in which they cause toxicity. Leukocytes can form reactive metabolites of drugs, which could obviously affect the immune system. They could also be responsible for bone marrow toxicity which is a relatively common serious idiosyncratic drug reaction. Most of our studies involve study of the formation of reactive metabolites of drugs by leukocytes and mechanisms by which such metabolites could be responsible for idiosyncratic drug reactions. These mechanistic studies utilize animal models and are principally immunologic in nature.