The role of reactive drug metabolites in immune-mediated adverse drug reactions

OBJECTIVE: To highlight recent advances in the understanding of adverse drug reactions (ADRs), with a fetus on models outlining interactions between drug metabolism, disease processes, and immunity. Specific mechanisms that identify the metabolic pathways responsible for drug bioactivation to reactive drug metabolites (RDMs) involved in the initiation and propagation of specific immune-mediated hypersensitivity reactions are discussed. Drug classes well known to be associated with immune-mediated ADRs are reviewed and the clinical implications of current research are discussed. DATA SOURCES: Original experimental research and immunologic review articles relevant to ADR diagnosis and etiology. DATA EXTRACTION: Results of relevant in vitro experiments and clinical reactions to drug therapy were compiled and reviewed. Critical discoveries concerning the identification of RDMs involved in ADRs were highlighted, with respect to RDM involvement in the production of an immune response to drug haptens. DATA SYNTHESIS: Drug adverse effects are classified according to clinical characteristics, immune interactions, and mechanistic similarities. Cytochrome P450 bioactivation of drug molecules to RDMs is a prerequisite to many ADRs. An electrophilic metabolite may react with cellular macromolecules (i.e., lipids, proteins, nucleic acids), resulting in direct cellular damage and organ toxicity. Covalent binding of an RDM to cellular macromolecules may also result in the formation of a hapten that is capable of eliciting a cellular or humoral immune response against drug or protein epitopes, culminating in the characteristic symptoms of hypersensitivity reactions. Mechanistic details concerning the identification of stable protein-metabolite conjugates and their interaction with the immune system remain unclear. Genetic imbalance between bioactivation and detoxification pathways, as well as reduced cellular defense against RDMs due to disease or concomitant drug therapy, act as risk factors to the onset and severity of ADRs. CONCLUSIONS: Adverse reactions to drug therapy cause significant morbidity and mortality. Identification of the pathways involved in drug bioactivation and detoxification may elucidate the potential of chemical agents to induce immune-mediated ADRs. Understanding the mechanisms of ADRs to current xenobiotics is helpful in the prevention and management of ADRs, and may prove useful in the design of novel therapeutic agents with reduced incidence of severe adverse events.