Idiosyncratic drug reactions: current understanding.
Clinical characteristics and circumstantial evidence suggest that idiosyncratic drug reactions are caused by reactive metabolites and are immune-mediated; however, there are few definitive data and there are likely exceptions. There are three principal hypotheses for how reactive metabolites might induce an immune-mediated idiosyncratic reaction: the hapten hypothesis, the danger hypothesis, and the PI hypothesis. It has been proposed that some idiosyncratic reactions, especially those involving the liver, represent metabolic idiosyncrasy; however, there are even less data to support this hypothesis. The unpredictable nature of these reactions makes mechanistic studies difficult. There is a very strong association with specific human leukocyte antigen (HLA) genes for certain reactions, but this has only been demonstrated for very few drugs. Animal models represent a very powerful tool for mechanistic studies, but the number of valid models is also limited. There may be biomarkers of risk; however, much more work needs to be done.
Uetrecht
Jack
J
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 2S2, Canada. jack.uetrecht@utoronto.ca
D016907:Adverse Drug Reaction Reporting Systems; D000818:Animals; D015415:Biomarkers; D064420:Drug-Related Side Effects and Adverse Reactions; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D023421:Models, Animal; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests
D015415:Biomarkers; D006680:HLA Antigens; D004364:Pharmaceutical Preparations