Exploring the Role of Metabolites in Torsadogenic Risk Assessment: A Text-Mining Approach

Objectives: Torsades de pointes (TdP) is a life-threatening ventricular arrhythmia often caused by the inadvertent inhibition of the human ether-à-go-go-related gene (hERG). Conventional pre-market evaluations, which emphasize parent molecules, often yield inaccurate predictions due to the multifaceted nature of TdP. This study aimed to investigate the role of metabolites and their interplay with parent molecules in the manifestation of TdP. Materials and Methods: A literature-based text-mining approach was employed, using the adverse outcome pathway-helpFinder tool. The analysis scrutinized 64 selected active ingredients, categorized by their torsadogenic risks, to evaluate the distinct proarrhythmic contributions of their metabolites. Results: This text-mining exploration revealed qualitative evidence that metabolites variably modulate TdP vulnerability. Specifically, certain metabolites can independently exacerbate proarrhythmic profiles, whereas others do not inhibit hERG and therefore represent safer therapeutic alternatives than their parent molecules. Conclusion: Metabolites play a paramount role in altering the torsadogenic risk profile of pharmaceutical products. Incorporating comprehensive metabolite data into cardiac safety evaluations is essential for a more accurate risk assessment and should be considered in future pharmaceutical development.