Neutral effects of the novel analgesic tapentadol on cardiac repolarization due to mixed ion channel inhibitory activities

Abstract

AbstractTapentadol is a novel analgesic with µ‐opioid receptor agonistic and norepinephrine reuptake inhibiting activities at submicromolar concentrations. Given that inhibition of cardiac potassium currents by noncardiovascular pharmaceuticals is a critical issue in drug development, the potential effects of tapentadol on myocardial repolarization were evaluated. Tapentadol concentration‐dependently inhibited hERG‐related currents in CHO cells with 250 and 750 times lower potency than haloperidol and sertindole. In electrically stimulated guinea pig papillary muscles, tapentadol at 10 and 100 µM shortened the action potential duration at 30% of repolarization (APD30) and APD90. Maximum effects (100 µM) were more pronounced on APD30 than on APD90. In contrast, the hERG inhibitor, d,l‐sotalol concentration‐dependently (1–100 nM) prolonged APD90 without affecting APD30. In isolated, perfused, spontaneously beating guinea pig hearts, volume‐conducted ECGs revealed that tapentadol reduced heart rate (HR) and prolonged uncorrected QT time, but did not affect HR‐corrected QTc time. The hERG inhibitor, dofetilide (0.01 and 0.1 µM) reduced HR and prolonged QT and QTc time. PR time was prolonged by tapentadol but not by dofetilide. Intravenous infusion of tapentadol (3, 6, 9mg/kg) in conscious dogs led to suprapharmacological plasma concentrations of up to 12 µM (2,531 ng/ml). QT time decreased in tapentadol‐treated dogs in parallel to an increase in HR, whereas HR‐corrected QTc time was not affected. In conclusion, the in vitro effects of tapentadol suggest mixed ion channel activities on potassium, calcium, and sodium channels at supra‐pharmacological concentrations. These activities may be neutralizing, resulting in lack of a net effect of tapentadol on cardiac repolarization. Drug Dev Res 1–12, 2010 © 2010 Wiley‐Liss, Inc.