title: Effects of probucol, a typical hERG expression inhibitor, on in vivo QT interval prolongation in conscious dogs.
abstract: 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 (<DELTA>QTc) interval and its integration from 1 to 21 h (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.
authors.affiliation: Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., 2399-1 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan. Electronic address: hisashi.nogawa@mb.kyorin-pharm.co.jp.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Nogawa
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kawai
authors.forename: Miho
authors.initials: M
authors.lastname: Yajima
authors.forename: Masahiro
authors.initials: M
authors.lastname: Miura
authors.forename: Tetsurou
authors.initials: T
authors.lastname: Ogawa
authors.forename: Kouji
authors.initials: K
authors.lastname: Murakami
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D001372:Aza Compounds / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D004285:Dogs; D004347:Drug Interactions; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D024841:Fluoroquinolones; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D000077266:Moxifloxacin; D011341:Probucol / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D011804:Quinolines / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D000924:Anticholesteremic Agents; D001372:Aza Compounds; D051638:Ether-A-Go-Go Potassium Channels; D024841:Fluoroquinolones; D011804:Quinolines; D011341:Probucol; D000077266:Moxifloxacin
keywords: Conscious dogs; Probucol; QT interval prolongation; hERG expression inhibitor