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.
Cho, TE, Uetrecht J. How reactive metabolites induce an immune response that sometimes leads to an idiosyncratic drug reaction. Chem. Res. Toxicol. 30(1):295-314, 2017.
Liu F, Cai P, Metushi I, Li Jinze, Nakayawa T, Vega L, Uetrecht J. Exploring an animal model of amodiaquine-induced liver injury in rats and mice. J. Immunotoxicol. 13(5): 694-712, 2016.
Mak A, Uetrecht J. The combination of anti-CTLA-4 and PD1-/- mice unmasks the potential of isoniazid and nevirapine to cause liver injury. Chem Res Toxicol. 28(12): 2287-2291, 2015.
Uetrecht J, Kaplowitz N. Inhibition of immune tolerance unmasks drug-induced allergic hepatitis. Hepatology. 62(2): 346-348, 2015.
Mak A, Uetrecht J. The role of CD8 T cells in amodiaquine-induced liver injury in PD1-/- mice cotreated with anti-CTLA-4. Chem Res Toxicol. 28(8): 1567-1573, 2015.
Mak A, Uetrecht J. Immunization with amodiaquine-modified hepatic proteins prevents amodiaquine-induced liver injury. J Immunotoxicol. 12(4): 361-367, 2015.
Johnston A, Uetrecht J. Current understanding of the mechanisms of idiosyncratic drug-induced-agranulocytosis. Expert Opinion on Drug Metabolism & Toxicology. 11(2):243-257, 2015.
Metushi IG, Hayes MA, Uetrecht J. Treatment of PD-1(-/-) mice with amodiaquine and anti-CTLA4 leads to liver injury similar to idiosyncratic liver injury in patients. Hepatology. 61(4):1332-1342, 2015.
Lobach A, Uetrecht J. Clozapine promotes the proliferation of granulocyte progenitors in the bone marrow leading to increased granulopoiesis and neutrophilia in rats. Chem Res Toxicol 27(7): 1109-1119, 2014.
Ng W, Kennar R, Uetrecht J. Effect of clozapine and olanzapine on neutrophil kinetics: implications for drug-induced agranulocytosis. Chem Res Toxicol 27(7): 1104-1108, 2014.
Weston JK, Uetrecht J. Activation of inflammasomes by agents causing idiosyncratic skin reactions: a possible biomarker. Chem. Res. Toxicol. 27(6): 949-951, 2014.
Metushi, IG, Lee WM, Uetrecht J. IgG3 is the dominant subtype of anti-isoniazid antibodies in patients with isoniazid-induced liver failure. Chem. Res. Toxicol. 27(5): 738-740, 2014.
Leslie Dan Faculty of Pharmacy
University of Toronto
144 College Street