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

Cardiovasc Toxicol. 2016 Apr;16(2):138-46. doi: 10.1007/s12012-015-9322-2.


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.

Keywords: Guinea pig; Halothane; Pharmacodynamics; Pharmacokinetics; QT-interval prolongation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anesthesia, Inhalation / methods
  • Animals
  • Anti-Arrhythmia Agents / pharmacokinetics
  • Anti-Arrhythmia Agents / pharmacology
  • Dose-Response Relationship, Drug
  • ERG1 Potassium Channel / antagonists & inhibitors*
  • ERG1 Potassium Channel / physiology
  • Electrocardiography / drug effects*
  • Guinea Pigs
  • Halothane / administration & dosage*
  • Heart Rate / drug effects*
  • Heart Rate / physiology
  • Male
  • Models, Animal*
  • Sotalol / pharmacokinetics
  • Sotalol / pharmacology*


  • Anti-Arrhythmia Agents
  • ERG1 Potassium Channel
  • KCNH2 protein, human
  • Sotalol
  • Halothane