Canada Research Chair in Adverse Drug Reactions
Toxicology and Drug Metabolism
The focus of my research involves the study of idiosyncratic drug reactions. These reactions are unexpected adverse reactions that occur in a small percentage of patients that take a drug. Idiosyncratic drug reactions can affect any organ but the skin, liver and bone marrow are the most common targets. Such reactions can also lead to autoimmune reactions that resemble lupus. Although the percentage of patients affected by any one drug is small, the total number of patients affected is large, and such reactions represent a serious medical problem. In addition, such reactions often lead to withdrawal or severe restrictions on the use of a drug, and this significantly adds to the uncertainty of drug development.
In general idiosyncratic drug reactions appear to be due to chemically reactive metabolites of a drug rather than to the drug itself. Therefore much or our work involves the identification of reactive metabolites of drugs and their reactions with biological molecules. Not all drugs that form reactive metabolites are associated with a high incidence of idiosyncratic drug reactions. One hypothesis that we are testing is that, in order to induce an idiosyncratic reaction, the reactive metabolite must not only covalently bind to protein but must also cause cell stress. Therefore, we are looking for markers of cell stress that will better predict which drug candidates will be associated with a high incidence of adverse reactions. Although most drug metabolism occurs in the liver, we have found that cells of the immune system, especially neutrophils and monocytes, which contain myeloperoxidase, can readily oxidize certain drugs to reactive metabolites. These same drugs can cause agranulocytosis, i.e. the neutrophils disappear. We make extensive use of mass spectrometry for metabolism studies.
Most idiosyncratic reactions appear to be mediated by the immune system; therefore, much of our work involves the study of the effects of reactive metabolites on the immune system. The immune system is quite complex and so such effects can not be duplicated in vitro. Although animals can have idiosyncratic reactions to drugs, they are just as idiosyncratic in animals as they are in humans, and so it is difficult to find suitable models in which a specific strain has a high incidence of an idiosyncratic reaction that is similar to the reaction that occurs in humans. However, we have discovered a few such animal models, and they are very useful for mechanistic studies. In some cases we can turn the adverse reactions on or off with simple treatments, and this provides clues as to risk factors for adverse reactions in humans. When possible we also try to extend our studies to humans because that is the real test as to whether the models truly reflect adverse reactions in humans.