Metabolic activation in drug allergies

• Published in: Toxicology (Amsterdam) Vol. 158; no. 1; pp. 11 - 23
• Main Authors: Park, B.K., Naisbitt, D.J., Gordon, S.F., Kitteringham, N.R., Pirmohamed, M.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Shannon Elsevier Ireland Ltd 02.02.2001; Amsterdam Elsevier Science
• Subjects: Adverse drug reaction; Allergy; Animals; Biological and medical sciences; Drug Eruptions - immunology; Drug Eruptions - metabolism; Drug Eruptions - pathology; Drug Hypersensitivity - etiology; Drug Hypersensitivity - metabolism; Drug Hypersensitivity - pathology; Drug toxicity and drugs side effects treatment; Drug-Related Side Effects and Adverse Reactions; Haptens; Hematologic Diseases - chemically induced; Hematologic Diseases - immunology; Hematologic Diseases - pathology; Humans; Hypersensitivity; Medical sciences; Miscellaneous (drug allergy, mutagens, teratogens...); Models, Animal; Pharmaceutical Preparations - metabolism; Pharmacology. Drug treatments; Toxicity Tests; Allergy; Hypersensitivity; Adverse drug reaction; Human; Drug; Immunopathology; Immune response; Enzyme; Metabolite; Toxicity; Metabolism; Hapten; Antigen; Immunogenicity; Metabolic activation; Secondary effect; Drug-metabolizing enzyme; Conjugated compound; Immune system
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/S0300-483X(00)00397-8

Drug allergies are a major problem in the clinic and during drug development. At the present time, it is not possible to predict the potential of a new chemical entity to produce an allergic reaction (hypersensitivity) in patients in preclinical development. Such adverse reactions, because of their idiosyncratic nature, only become apparent once the drug has been licenced. Our present chemical understanding of drug hypersensitivity is based on the hapten hypothesis, in which covalent binding of the drug (metabolite) plays a central role in drug immunogenicity and antigenicity. If this theory is correct, then it should be possible to develop in vitro systems to assess the potential of drugs to bind to critical proteins, either directly or indirectly after metabolic activation to protein-reactive metabolites (bioactivation) and initiate hypersensitivity. The purpose of this review is to assess critically the evidence to support the hapten mechanism, and also to consider alternative mechanisms by which drugs cause idiosyncratic toxicity.