Why Can dl-Sotalol Prolong the QT Interval In Vivo Despite Its Weak Inhibitory Effect on hERG K⁺ Channels In Vitro? Electrophysiological and Pharmacokinetic Analysis with the Halothane-Anesthetized Guinea Pig Model

In order to bridge the gap of action of dl-sotalol between the human ether-a-go-go-related gene (hERG) K⁺ channel inhibition in vitro and QT-interval prolongation in vivo, its electropharmacological effect and pharmacokinetic property were simultaneously studied in comparison with those of 10 drugs having potential to prolong the QT interval (positive drugs: bepridil, haloperidol, dl-sotalol, terfenadine, thioridazine, moxifloxacin, pimozide, sparfloxacin, diphenhydramine, imipramine and ketoconazole) and four drugs lacking such property (negative drugs: enalapril, phenytoin, propranolol or verapamil) with the halothane-anesthetized guinea pig model. A dose of each drug that caused 10 % prolongation of Fridericia-corrected QT interval (QTcF) was calculated, which was compared with respective known hERG K⁺ IC₅₀ value and currently obtained heart/plasma concentration ratio. Each positive drug prolonged the QTcF in a dose-related manner, whereas such effect was not observed by the negative drugs. Drugs with more potent hERG K⁺ channel inhibition showed higher heart/plasma concentration ratio, resulting in more potent QTcF prolongation in vivo. The potency of dl-sotalol for QTcF prolongation was flat middle, although its hERG K⁺ channel inhibitory property as well as heart/plasma concentration ratio was the smallest among the positive drugs, which may be partly explained by its lack of binding to plasma protein.