The role of active metabolites in drug toxicity

Adverse drug reactions can be caused by the parent drug or a metabolite of that drug. The metabolite may be stable or chemically reactive, the resultant toxicity being either a direct extension of the pharmacology of the drug, or unrelated to the known pharmacology of the drug and dependent on the chemical properties of the compound. Many different organ systems may be affected, and there are several mechanisms involved in determining organ-specific, and sometimes cell-selective, toxicity. An imbalance between bioactivation of a drug to a toxic metabolite and its detoxification is of prime importance in determining individual susceptibility. Such an imbalance may be genetically determined or acquired and, furthermore, may be systemic or tissue-specific. Prevention of metabolite-mediated toxicity is possible once the mechanism of toxicity has been elucidated.