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Verapamil is a well-known and world-wide prescribed calcium antagonist, but it suffers from extensive first-pass metabolism. Although it has been marketed for many years, a complete understanding of its biotransformation in humans is still lacking.The metabolism of verapamil was therefore investigated in cultures of primary human hepatocytes and in extracts of human urine after oral dosing. Identification of metabolites was done with LC-MSn and LC-NMR (600 MHz) toobtain in-depth information on its biotransformation products and definitive proof of the proposed chemical structures of metabolites.Hyphenation of LC-MSn and LC-NMR was shown to be a powerful and effective platform for the identification of metabolites. Indeed, 21 Phase I and 16 Phase II metabolites were identified. Basically, all the Phase II metabolites (glucuronides) and 11 of the Phase I (oxidative) metabolites were not reported previously.New insight into verapamil's biotransformation pathway is provided as well as evidence about its true complexity of metabolic disposal.