Effects of probucol, a typical hERG expression inhibitor, on in vivo QT interval prolongation in conscious dogs

• Published in: European journal of pharmacology 2013-11, Vol.720 (1-3), p.29-37
• Main Authors: Nogawa, Hisashi, Kawai, Tomoyuki, Yajima, Miho, Miura, Masahiro, Ogawa, Tetsurou, Murakami, Kouji
• Format: Article
• Language: English
• Subjects: additive effect; Animals; anticholesteremic agents; Anticholesteremic Agents - adverse effects; Anticholesteremic Agents - blood; Anticholesteremic Agents - pharmacokinetics; Aza Compounds - adverse effects; Aza Compounds - blood; Aza Compounds - pharmacokinetics; chronic exposure; Conscious dogs; Dogs; Drug Interactions; electrocardiography; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors; Fluoroquinolones; genes; hERG expression inhibitor; humans; in vitro studies; Long QT Syndrome - chemically induced; Male; patients; plasma membrane; Probucol; Probucol - adverse effects; Probucol - blood; Probucol - pharmacokinetics; QT interval prolongation; Quinolines - adverse effects; Quinolines - blood; Quinolines - pharmacokinetics
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2013.10.056

The cholesterol-lowering drug, probucol, is known to induce QT interval prolongation and torsades de pointes in patients. Recent in vitro studies have indicated that probucol reduces hERG expression in the plasma membrane and does not directly block human ether-a-go-go-related gene (hERG) channels. The present study was performed to investigate the effects of probucol on in vivo QT interval prolongation. Epicardial electrocardiograms were recorded in conscious dogs given oral single or repeated (7 days) doses of probucol (100mg/kg), and in combination with moxifloxacin (20mg/kg). QTc intervals were analyzed by a probabilistic method with individual rate collection formulae. Values of change in QTc ( QTc) interval and its integration from 1 to 21h (AUC1–21h) were calculated to evaluate drug-induced QT prolongation. A single dose of probucol slightly but significantly increased the AUC1–21h QTc interval on days 2 and 3. The QT prolongation was markedly augmented by repeated doses of probucol in a time-dependent manner, despite the lack of increase in plasma concentration. The combination of probucol and moxifloxacin produced additive effects on QT interval prolongation. These results suggest that long-term exposure to the hERG expression inhibitor, probucol, is required to evaluate its maximal effects on in vivo QT interval prolongation. A combination of direct and indirect hERG inhibitors may produce simple additive effects on QT interval prolongation.