title: 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.
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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Katagi
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan. yuuji.nakamura@med.toho-u.ac.jp.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan.
authors.forename: Xin
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan.|Division of Cardiovascular Medicine, Department of Internal Medicine, Faculty of Medicine, Toho University, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohara
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Honda
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Izumi-Nakaseko
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ando
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan. atsushi.sugiyama@med.toho-u.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sugiyama
mesh_terms: D000769:Anesthesia, Inhalation / Q000379:methods; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel / Q000037:antagonists & inhibitors* / Q000502:physiology; D004562:Electrocardiography / Q000187:drug effects*; D006168:Guinea Pigs; D006221:Halothane / Q000008:administration & dosage*; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D008297:Male; D023421:Models, Animal; D013015:Sotalol / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human; D013015:Sotalol; D006221:Halothane
keywords: Guinea pig; Halothane; Pharmacodynamics; Pharmacokinetics; QT-interval prolongation