Mechanisms of idiosyncratic hypersensitivity reactions to antiepileptic drugs.
Hypersensitivity reactions to the aromatic antiepileptic drugs (AEDs) phenytoin (PHT) and carbamazepine (CBZ) appear to have an immune etiology. Current models of drug hypersensitivity center around the concept of drug bioactivation to reactive metabolites that irreversibly modify cellular proteins. These modified proteins are believed to initiate (or serve as targets of) an autoimmune-like attack on specific drug-modified proteins in target organs (e.g., liver, skin) of susceptible individuals. Consistent with this model, antibodies to drug-modified and native proteins have been identified in the sera of patients experiencing several drug hypersensitivity reactions. New models must incorporate an understanding of the mechanisms by which drug-modified proteins are processed and presented to the immune system in the appropriate context to culminate in the clinical manifestations of "hypersensitivity." Idiosyncratic toxicities associated with new AEDs, such as lamotrigine and felbamate, appear mechanistically distinct from PHT and CBZ hypersensitivity but may involve similar processes: bioactivation, detoxification, covalent adduct formation, processing and presentation of antigen to the immune system, and consequent formation of antibody and T-cell immune effectors. The goal of research is to develop a "susceptibility profile" for identifying individuals at risk for these forms of drug toxicity.
Leeder
J S
JS
The Children's Mercy Hospital, Department of Pediatrics, University of Missouri-Kansas City, 64108, USA.
D000927:Anticonvulsants / Q000009:adverse effects* / Q000276:immunology / Q000627:therapeutic use; D001711:Biotransformation; D002220:Carbamazepine / Q000009:adverse effects; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000276:immunology; D004342:Drug Hypersensitivity / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D004827:Epilepsy / Q000188:drug therapy; D005838:Genotype; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D018448:Models, Immunological; D010672:Phenytoin / Q000009:adverse effects; D011110:Polymorphism, Genetic
D000927:Anticonvulsants; D002220:Carbamazepine; D010672:Phenytoin; D003577:Cytochrome P-450 Enzyme System