Faculty: Jack P. Uetrecht, MD, PhD
General Research Areas: Clinical Pharmacology and Toxicology
Idiosyncratic Drug Reactions
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.
Uetrecht J. Idiosyncratic drug reactions: past, present, and future. Chem Res Toxicol. 2008 Jan 21;21(1):84-92. Epub 2007 Dec 4.
Lu W, Uetrecht JP. Possible bioactivation pathways of lamotrigine. Drug Metab Dispos. 2007 Jul;35(7):1050-6. Epub 2007 Apr 4.
Uetrecht J. Idiosyncratic drug reactions: current understanding. Annu Rev Pharmacol Toxicol. 2007;47:513-39.
Uetrecht J. Evaluation of which reactive metabolite, if any, is responsible for a specific idiosyncratic reaction. Drug Metab Rev. 2006;38(4):745-53.
Popovic M, Caswell JL, Mannargudi B, Shenton JM, Uetrecht JP. Study of the sequence of events involved in nevirapine-induced skin rash in Brown Norway rats. Chem Res Toxicol. 2006 Sep;19(9):1205-14.
Uetrecht J. Role of animal models in the study of drug-induced hypersensitivity reactions. AAPS J. 2006 Jan 13;7(4):E914-21. Review.
Shenton JM, Popovic M, Chen J, Masson MJ, Uetrecht JP. Evidence of an immune-mediated mechanism for an idiosyncratic nevirapine-induced reaction in the female Brown Norway rat. Chem Res Toxicol. 2005 Dec;18(12):1799-813.
Pearce RE, Uetrecht JP, Leeder JS. Pathways of carbamazepine bioactivation in vitro: II. The role of human cytochrome P450 enzymes in the formation of 2-hydroxyiminostilbene. Drug Metab Dispos. 2005 Dec;33(12):1819-26. Epub 2005 Aug 31.
Séguin B, Boutros PC, Li X, Okey AB, Uetrecht JP. Gene expression profiling in a model of D-penicillamine-induced autoimmunity in the Brown Norway rat: predictive value of early signs of danger. Chem Res Toxicol. 2005 Aug;18(8):1193-202.
Leslie Dan Faculty of Pharmacy
University of Toronto
144 College Street