Mechanisms of drug reactions: the metabolic track

Hypersensitivity syndrome (HSR) describes a drug-induced symptom complex consisting of fever, rash, and internal organ involvement. Although these reactions are rare, they are very important because of their severity and unpredictability. The metabolic conversion of drugs to chemically-reactive products is now established as a prerequisite for many idiosyncratic drug reactions. In the setting of HSR, an imbalance in the rates of formation of reactive metabolites and of enzymatic detoxification can lead to accumulation of these byproducts. Reactive metabolites could act as haptens eliciting an immune response, covalently bind target proteins causing cell death, or interact with nucleic acids leading to mutations. The lymphocyte toxicity assay (LTA) provides an in vitro assessment of host susceptibility to reactive metabolites of a given drug. It has validated the clinical finding of increased risk of HSR in first degree relatives of patients. It is hoped that the LTA will be used to predict host susceptibility before drug exposure. Ultimately it is hoped that the genetic defects that lead to drug reactions will be identified. This would improve drug development safety and allow primary prevention of serious reactions.