Metabolic bioactivation of antidepressants: advance and underlying hepatotoxicity

Many drugs that serve as first-line medications for the treatment of depression are associated with severe side effects, including liver injury. Of the 34 antidepressants discussed in this review, four have been withdrawn from the market due to severe hepatotoxicity, and others carry boxed warnings for idiosyncratic liver toxicity. The clinical and economic implications of antidepressant-induced liver injury are substantial, but the underlying mechanisms remain elusive. Drug-induced liver injury may involve the host immune system, the parent drug, or its metabolites, and reactive drug metabolites are one of the most commonly referenced risk factors. Although the precise mechanism by which toxicity is induced may be difficult to determine, identifying reactive metabolites that cause toxicity can offer valuable insights for decreasing the bioactivation potential of candidates during the drug discovery process. A comprehensive understanding of drug metabolic pathways can mitigate adverse drug-drug interactions that may be caused by elevated formation of reactive metabolites. This review provides a comprehensive overview of the current state of knowledge on antidepressant bioactivation, the metabolizing enzymes responsible for the formation of reactive metabolites, and their potential implication in hepatotoxicity. This information can be a valuable resource for medicinal chemists, toxicologists, and clinicians engaged in the fields of antidepressant development, toxicity, and depression treatment.