Electrophysiological safety of novel fluoroquinolone antibiotic agents gemifloxacin and balofloxacin.
Some fluoroquinolones have been reported to induce QT interval prolongation associated with the onset of torsades de pointes (TdP), resulting in a life-threatening ventricular arrhythmia. We investigated the cardiac electrophysiological effects of two new fluoroquinolones, gemifloxacin and balofloxacin, by using conventional microelectrode recording techniques in isolated rabbit Purkinje fiber and whole-cell patch-clamp techniques in human ether-á-go-go related gene (hERG)-transient transfected CHO cells. Gemifloxacin had no significant effects on the resting membrane potential, total amplitude, action potential, and Vmax of phase 0 depolarization at concentrations up to 30 microM, but gemifloxacin at 100 microM significantly decreased total amplitude (p < 0.01). These values of gemifloxacin (30 and 100 microM) were approximately 25- and 83-fold more than the free plasma concentration of 1.2 microM in a single therapeutic injection in humans. For I(hERG), the IC(50) value was about 300 microM. Balofloxacin had also no significant effects on the resting membrane potential, total amplitude, action potential duration, and Vmax of phase 0 depolarization at concentrations up to 30 microM, but balofloxacin at 100 microM significantly (p < 0.01) prolonged action potentials at both 50% repolarization (APD(50)) and 90% repolarization (APD(90)). These values of balofloxacin (30 and 100 microM) were approximately 6.8- and 23-fold more than the free plasma concentration of 4.4 microM in a single therapeutic injection in humans. For I(hERG), the IC(50) value was 214 +/- 14 microM. Therefore, our data suggested that in the electrophysiological aspect, gemifloxacin and balofloxacin may have no torsadogenic potenties up to 30 microM.
Seop Kim
Dong
D
Division of General Pharmacology, National Institute of Toxicological Research, Eunpyeong, Seoul, Korea.
Kim
Ki-Suk
KS
Hwan Choi
Ki
K
Na
Hankwang
H
Kim
Joo-Il
JI
Shin
Won-Ho
WH
Kim
Eun-Joo
EJ
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D001682:Biological Availability; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D005260:Female; D024841:Fluoroquinolones / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D000077735:Gemifloxacin; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D009287:Naphthyridines / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D026902:Potassium Channel Blockers; D011690:Purkinje Fibers / Q000187:drug effects; D011817:Rabbits
D000900:Anti-Bacterial Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D024841:Fluoroquinolones; C000606913:KCNH2 protein, human; D009287:Naphthyridines; D026902:Potassium Channel Blockers; D000077735:Gemifloxacin; C077155:balofloxacin