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AASLD-FDA-NIH-PhRMA Hepatotoxicity Steering Group Meeting, 2006 Presentations: Tolerance

Jack Uetrecht, MD, PhD
University of Toronto
Tolerance [PDF]

Little is known about the mechanisms of idiosyncratic drug reactions. The characteristics of idiosyncratic reactions suggest that these adverse reactions are immune-mediated; however, the evidence in most cases is quite weak, and it is likely that some idiosyncratic reactions are not immune-mediated. On the other hand, there is even less evidence for the concept of metabolic idiosyncrasy. One characteristic is that the reaction often resolves despite continued treatment with the drug. This is seen in liver injury with an increase in transaminases followed by return to normal with no clinical evidence of toxicity. It is frequently seen in skin rashes in which a mild drug rash will resolve despite continued treatment. It is sometimes seen with drug-induced agranulocytosis in which the neutrophil count returns to normal in a shorter time period than seems possible for the half-life of the drug and the time required to generate neutrophils. One possible reason for this observation is immune tolerance. In general the immune system performs a delicate balancing act between an active immune response and tolerance. It is possible that most patients who are given a drug that causes an idiosyncratic response in some patients develop immune tolerance, and it is only the few who do not develop tolerance who have an adverse reaction. How can this hypothesis be tested?

The idiosyncratic nature of these reactions make them very difficult to study in humans. Animal models provide an important resource, but idiosyncratic reactions are also idiosyncratic in animals, and to be useful, the mechanism in the animal model must be the same, or at least very similar, to the reaction in humans. We have two animal models of idiosyncratic drug reactions with characteristics very similar to the reactions that occur in humans: penicillamine-induced autoimmunity (including liver necrosis) in the Brown Norway rat and nevirapine-induced rash in the rat. Both are clearly immune-mediated. In both cases low dose treatment (half of the dose that leads to an adverse reaction) with the drug for 2 weeks prior to the full dose leads to tolerance. In the penicillamine model this is immune tolerance and can be transferred to naïve animals with T cells. When tolerized animals are treated with high dose penicillamine, their CD4+ T cells produce IL-10 and TGF-ß consistent with the tolerance being mediated by regulatory T cells. In contrast most of the tolerance in the nevirapine model is metabolic tolerance, i.e. the low dose induces P450 and then when the animal is given the higher dose the blood levels are much lower than when a naïve animal is started on high dose. This tolerance is not long lasting and can be overcome by P450 inhibition. It appears that immune tolerance can also be induced by a long period of treatment during which the immune response is suppressed with tacrolimus. There are also several other striking differences in the characteristics of these two models. Thus there are likely several mechanisms for idiosyncratic reactions and tolerance. Although valid animal models of idiosyncratic reactions are very difficult to develop, they represent a very powerful way to study mechanism.

Biographical Sketch

Jack Uetrecht received his Ph.D. in Organic Chemistry from Cornell University in 1972, an M.D. from Ohio State University of 1975 and, after a medical residency, a Clinical Pharmacology Fellowship at Vanderbilt University under the supervision of John Oates in 1981.

Professional Experience: Presently he is a Professor of Pharmacy and Medicine and Canada Research Chair in Adverse Drug Reactions at the University of Toronto. Previously he was the Associate Dean of Pharmacy (1994-1998) and Associate Professor of Pharmacy and Medicine University of Toronto (1985-1993); Assistant Professor of Pharmacology and Medicine, Vanderbilt University (1981-1985).

Research Interests: Mechanisms of idiosyncratic drug reactions with a focus on involvement of the immune system, reactive metabolites and the use of animal models with an extension to human idiosyncratic drug reactions.

Professional Societies and Activities: Chair, Pharmaceutical Sciences grant review committee for the Medical Research Council of Canada (1987-1991); Chair, Gordon Conference on Drug Metabolism (2002); Co-chair of new Gordon Conference on Adverse Drug Reactions (2005); Councilor, ISSX (1991-1994); Councilor, International Union of Pharmacology, Drug Metabolism Section (1992-1998); Editorial Boards: Chemical Research in Toxicology (1992-1997), Chemico-Biological Interactions (1992-1997), Drug Metabolism and Disposition (1997-present), Current Drug Metabolism (1999-present); Journal of Immuntoxicology (2003-present).