MECHANISMS OF DRUG-REACTIONS - THE METABOLIC TRACK

Hypersensitivity syndrome reaction (HSR) de scribes a drug induced sym ptom complex consisting of fever, rash, and internal organ involvement . Although these reactions are rare, they are very important because o f their severity and unpredictability. The metabolic conversion of dru gs to chemically reactive products is now established as a prerequisit e for many idiosyncratic drug reactions. In the setting of HSR, an imb alance in the rates of formation of reactive metabolites and of enzyma tic detoxification can lead to accumulation of these byproducts. React ive metabolites could act as haptens eliciting an immune response, cov alently bind target proteins causing cell death, or interact with nucl eic acids leading to mutations. The lymphocyte toxicity assay (LTA) pr ovides an in vitro assessment of host susceptibility to reactive metab olites of a given drug. It has validated the clinical finding of incre ased risk of HSR in first degree relatives of patients. It is hoped th at the LTA will be used to predict host susceptibility before drug exp osure. Ultimately it is hoped that the genetic defects that lead to dr ug reactions will be identified. This would improve drug develop ment safety and allow primacy prevention of serious reactions. Copyright (C ) 1996 by W.B. Saunders Company.