Comparative assessment of prurifloxacin, sparfloxacin, gatifloxacin and levofloxacin in the rabbit model of proarrhythmia.
The administration of certain quinolone antibiotics has been associated with a prolongation of the QT interval on electrocardiogram, and in rare cases ventricular arrhythmias such as torsades de pointes. In this in vivo study using a rabbit arrhythmia model, we assessed the proarrhythmic effects and changes in the QT interval elicited by the administration of NM394 (UFX), an active metabolite of the new quinolone antibiotic prulifloxacin, and three representative quinolones, sparfloxacin (SPFX), gatifloxacin (GFLX) and levofloxacin (LVFX). Chloralose-anesthetized rabbits were co-administered a continuous infusion of methoxamine (15 microg/kg/min) together with NaOH (vehicle, 0.2 mol/L), SPFX (2, 3, 4 mg/kg/min), GFLX (4 mg/kg/min), LVFX (4 mg/kg/min) or UFX (4 mg/kg/min) via the ear vein, and then the effects on electrocardiogram were examined. SPFX and GFLX both prolonged the QT and QTc intervals. GFLX also induced premature ventricular contractions in all 6 rabbits that received it, and subsequently it induced torsades de pointes (TdP) in 3 of the 6 rabbits. SPFX infused at the dose of 4 mg/ kg/min induced conduction blocks without inducing TdP, whereas that infused at the lower dose of 3 mg/ kg/min induced both conduction blocks and TdP. The infusions with LVFX and UFX did not elicit remarkable prolongations in the QT interval, and none of the animals infused with the agents developed arrhythmia. These findings suggested that LVFX and UFX were less potent than SPFX and GFLX in prolonging the QT interval and inducing life-threatening arrhythmias.
Akita
Megumi
M
Toxicology Laboratory, Pharmaceutical Development Department, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan.
Shibazaki
Yoshiaki
Y
Izumi
Masaaki
M
Hiratsuka
Kazuyuki
K
Sakai
Toki
T
Kurosawa
Tohru
T
Shindo
Yasuhiro
Y
D000818:Animals; D000890:Anti-Infective Agents / Q000633:toxicity*; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D015363:Quinolones / Q000633:toxicity*; D011817:Rabbits; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology
D000890:Anti-Infective Agents; D015363:Quinolones