title: Fluvoxamine by itself has potential to directly induce long QT syndrome at supra-therapeutic concentrations.
abstract: Fluvoxamine is one of the typical selective serotonin-reuptake inhibitors. While its combined use with QT-prolonging drugs has been contraindicated because of the increase in plasma concentrations of such drugs, information is still limited whether fluvoxamine by itself may directly prolong the QT interval. We examined electropharmacological effects of fluvoxamine together with its pharmacokinetic profile by using the halothane-anesthetized dogs (n = 4). Fluvoxamine was intravenously administered in three escalating doses of 0.1, 1 and 10 mg/kg over 10 min with a pause of 20 min between the doses. The low dose provided therapeutic plasma drug concentration, whereas the middle and high doses attained approximately 10 and 100 times of the therapeutic ones, respectively. Supra-therapeutic concentration of fluvoxamine exerted the negative chronotropic, inotropic and hypotensive effects; and suppressed the atrioventricular nodal and intraventricular conductions, indicating inhibitory actions on Ca2+ and Na+ channels, whereas it delayed the repolarization in a reverse use-dependent manner, reflecting characteristics of rapidly activating delayed rectifier K+ current channel-blocking property. Fluvoxamine prolonged the terminal repolarization phase at 100 times higher concentration than the therapeutic, indicating its proarrhythmic potential. Thus, fluvoxamine by itself has potential to directly induce long QT syndrome at supra-therapeutic concentrations.
authors.affiliation: Department of Pharmacology 143-8540; Division of Cardiovascular Medicine, Department of Internal Medicine, Toho University, Faculty of Medicine, 6-11-1 Omori-Nishi, Ota-ku, Tokyo 143-8541, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Yamazaki-Hashimoto
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohara
authors.forename: Xin
authors.initials: X
authors.lastname: Cao
authors.forename: Ken
authors.initials: K
authors.lastname: Kitahara
authors.forename: Hiroko
authors.initials: H
authors.lastname: Izumi-Nakaseko
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ando
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Takanori
authors.initials: T
authors.lastname: Ikeda
authors.forename: Junichi
authors.initials: J
authors.lastname: Yamazaki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sugiyama
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D015220:Calcium Channels / Q000187:drug effects; D000075202:Contraindications; D003864:Depression, Chemical; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D016666:Fluvoxamine / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D006329:Heart Conduction System / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced; D007262:Infusions, Intravenous; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D015222:Sodium Channels / Q000187:drug effects
chemical_list: D015220:Calcium Channels; D016666:Fluvoxamine; D017367:Selective Serotonin Reuptake Inhibitors; D015222:Sodium Channels