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Idiosyncratic Drug Reactions: Current Understanding.

Uetrecht J

Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, M5S 2S2, Canada jack.uetrecht@utoronto.ca.

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. Expected online publication date for the Annual Review of Pharmacology and Toxicology Volume 47 is January 6, 2007. Please see http://www.annualreviews.org/catalog/pub_dates.asp for revised estimates.

Published 1 August 2006 in Annu Rev Pharmacol Toxicol.
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