Metabolite-centric perspectives on QT prolongation: Molecular mechanisms and clinical implications beyond the parent drug.

Prolongation of the heart-rate-corrected QT interval is a widely accepted surrogate for delayed ventricular repolarization and torsade de pointes risk. Although initial drug-safety efforts targeted parent compounds, accumulating evidence shows that circulating and tissue-accumulated metabolites are often the primary drivers of heart-rate-corrected QT interval change. This review synthesizes mechanistic, translational, and clinical findings to explain how metabolites prolong QT through several routes: direct human ether-à-go-go-related gene and other ion-channel inhibition, modulation of sodium and potassium currents, interference with channel trafficking, and transcriptional remodeling. Case studies across antimalarials, psychotropics, tuberculosis regimens, opioids, and oncology agents consistently demonstrate stronger exposure-response relations for metabolites than for their parent drugs. Advances in pharmacokinetic-pharmacodynamic modeling, active-moiety concentration-QT assessment, and time-varying QT correction now allow more precise risk quantification and dose individualization. In parallel, genetic variability in enzymes such as cytochrome P450 2B6 and cytochrome P450 2D6, transporter polymorphisms in ABCB1, and drug-specific myocardial distribution patterns help explain interindividual susceptibility. Clinically, metabolite-aware drug selection within a class, dosing, scheduled electrocardiographic monitoring, and judicious management of drug interactions can mitigate arrhythmic risk without sacrificing therapeutic benefit. Future progress will depend on the routine incorporation of metabolite profiling and pharmacogenetic data into both drug development and patient care to advance precision cardiology.