Drug-Drug Interactions: Toxicological Perspectives
Major problems facing the pharmaceutical industry include loss of drug candidates due to preclinical toxicology and unanticipated adverse drug reactions after the introduction of new drugs into clinical practice (1). Most adverse drug reactions occur in only a small percentage of patients and are termed idiosyncratic, and many of these reactions are caused by reactive metabolites formed from drugs (2-4). Reactions of reactive metabolites with tissue macromolecules can lead to direct or intrinsic toxic effects and/or cause toxicity by forming haptens that lead to immunotoxic effects. Although new animal models are being developed that provide insights into factors that play a role in these idiosyncratic toxicities (5-7), no generally useful models are yet available.