Da. Hess et Mj. Rieder, THE ROLE OF REACTIVE DRUG METABOLITES IN IMMUNE-MEDIATED ADVERSE DRUG-REACTIONS, The Annals of pharmacotherapy, 31(11), 1997, pp. 1378-1387
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.