THE ROLE OF REACTIVE DRUG METABOLITES IN IMMUNE-MEDIATED ADVERSE DRUG-REACTIONS

OBJECTIVE: To highlight recent advances in the understanding of advers e drug reactions (ADRs), with a fetus on models outlining interactions between drug metabolism, disease processes, and immunity. Specific me chanisms that identify the metabolic pathways responsible for drug bio activation to reactive drug metabolites (RDMs) involved in the initiat ion and propagation of specific immune-mediated hypersensitivity react ions are discussed. Drug classes well known to be associated with immu ne-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 clinic al reactions to drug therapy were compiled and reviewed. Critical disc overies concerning the identification of RDMs involved in ADRs were hi ghlighted, with respect to RDM involvement in the production of an imm une 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 met abolite may react with cellular macromolecules (i.e., lipids, proteins , nucleic acids), resulting in direct cellular damage and organ toxici ty. Covalent binding of an RDM to cellular macromolecules may also res ult in the formation of a hapten that is capable of eliciting a cellul ar or humoral immune response against drug or protein epitopes, culmin ating in the characteristic symptoms of hypersensitivity reactions. Me chanistic details concerning the identification of stable protein-meta bolite conjugates and their interaction with the immune system remain unclear. Genetic imbalance between bioactivation and detoxification pa thways, as well as reduced cellular defense against RDMs due to diseas e or concomitant drug therapy, act as risk factors to the onset and se verity of ADRs. CONCLUSIONS: Adverse reactions to drug therapy cause s ignificant morbidity and mortality. Identification of the pathways inv olved in drug bioactivation and detoxification may elucidate the poten tial of chemical agents to induce immune-mediated ADRs. Understanding the mechanisms of ADRs to current xenobiotics is helpful in the preven tion and management of ADRs, and may prove useful in the design of nov el therapeutic agents with reduced incidence of severe adverse events.