Perspectives in Pharmacology Inflammation and Drug Idiosyncrasy—Is There a Connection?

“Drug idiosyncrasy” refers to untoward reactions to drugs that occur in a small fraction of patients and have no obvious relationship to dose or duration of therapy. The liver is a frequent target for toxicity. Much of the conventional thinking about mechanisms of drug idiosyncrasy has centered on hypotheses that the reactions have a metabolic basis involving drug metabolism polymorphisms or that they arise from a specific immune response to the drug or its metabolite(s). For very few drugs does convincing evidence exist for either of these mechanisms, however. The erratic temporal and dose relationships that characterize idiosyncratic drug responses suggest the possibility that some event during the course of therapy renders tissues peculiarly susceptible to toxic effects of the drug. For example, episodes of inflammation are commonplace in people, and results of numerous studies in animals indicate that a modest inflammatory response can enhance tissue sensitivity to a variety of toxic chemicals. These observations have led to the hypothesis that an episode of inflammation during drug therapy could decrease the threshold for drug toxicity and thereby render an individual susceptible to a toxic reaction that would not otherwise occur (i.e., an “idiosyncratic” response). This hypothesis can explain the features of drug idiosyncrasy using fundamental pharmacologic principles, and results of recent animal studies are supportive of this. Knowledge gaps that need to be filled before the hypothesis should be widely accepted are discussed. Idiosyncratic Reactions to Drugs Adverse drug reactions are an important source of morbidity and mortality in people. For example, a meta-analysis of 39 prospective studies revealed over 2 million cases of hospitalization and more than 100,000 deaths due to adverse drug reactions in the U.S. in 1994 (Lazarou et al., 1998). Idiosyncratic responses to drugs are one type of adverse drug reaction. For purposes of this commentary, “drug idiosyncrasy” is defined as an adverse reaction that does not arise from drugdrug interaction and that meets several criteria. Unlike typical toxic responses to xenobiotic agents, which are doserelated and unfold in a characteristic temporal pattern, idiosyncratic drug reactions 1) occur in a small fraction of people exposed to the drug (usually !5%), 2) are typically unrelated to the drug’s pharmacologic effect, 3) demonstrate no obvious relation to dose, and 4) occur with inconsistent temporal patterns in relation to drug exposure (Zimmerman, 1993). Since these reactions occur with low incidence in animals as they do in humans, they are not usually predicted from results of preclinical testing in which relatively small groups of animals are used. Some patients who respond idiosyncratically do so after the first or second administration of the drug, whereas others require weeks or months of therapy. Although idiosyncratic reactions can involve numerous tissues, the liver is commonly a target. Idiosyncratic drug reactions have obvious importance to human health. The type and severity of the reactions vary with the drug and the affected individual, but some result in permanent disability or death. In addition to having direct effects on human health, these adverse drug reactions have resulted in removal from the market of otherwise efficacious drugs, which had the potential to improve human health and reduce suffering. Because of the infrequency of their occurrence and the lack of animal models for preclinical evaluation, idiosyncratic reactions are typically not discovered until a drug is in phase 2 clinical trials or actually on the market Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. DOI: 10.1124/jpet.102.041624. ABBREVIATIONS: GGT, !-glutamyl transferase; INH, isoniazid; LPS, lipopolysaccharide; TNF-", tumor necrosis factor-"; COX2, cyclooxygenase-2; MCT, monocrotatline; ALT, alanine aminotransferase; CPZ, chlorpromazine; RAN, ranitidine; HPCs, hepatic parenchymal cells; AFB1, aflatoxin B1. 0022-3565/03/3071-1–8$7.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 307, No. 1 Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics 41624/1095053 JPET 307:1–8, 2003 Printed in U.S.A.