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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

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Abstract

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.

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Acknowledgments

This study was supported in part by Grant-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology in Japan (#25460344, #S1101016), Japan Science and Technology Agency (#AS2116907E), and Toho University Joint Research Fund (H25-3, H26-2). The authors thank Dr. Akira Akimoto and Ms. Misako Nakatani for their technical supports.

Conflict of interest

The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan

    Jun Katagi, Yuji Nakamura, Xin Cao, Hiroshi Ohara, Atsushi Honda, Hiroko Izumi-Nakaseko, Kentaro Ando & Atsushi Sugiyama

  2. Division of Cardiovascular Medicine, Department of Internal Medicine, Faculty of Medicine, Toho University, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan

    Hiroshi Ohara

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  1. Jun Katagi
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  2. Yuji Nakamura
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  3. Xin Cao
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Correspondence to Yuji Nakamura or Atsushi Sugiyama.

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Katagi, J., Nakamura, Y., Cao, X. et al. 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 16, 138–146 (2016). https://doi.org/10.1007/s12012-015-9322-2

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