Electrophysiological safety of DW-286a, a novel fluoroquinolone antibiotic agent.
Inhibition of the potassium current I(Kr) and QT prolongation has been known to be associated with drug-induced torsades de pointes arrhythmias (TdP) and sudden cardiac death. We investigated the cardiac electrophysiological effects of DW-286a, a new class of fluoroquinolone antibiotics reported to prolong the QT interval. To investigate the electrophysiological safety of DW-286a, we used conventional microelectrode recording techniques in isolated guinea pig papillary muscles, whole-cell patch clamp techniques in human ether-à-go-go related gene (hERG)-transient transfected Chinese hamster ovary cells, and in vivo electrocardiogram (ECG) measurements in Sprague-Dawley (SD) rats by the use of a telemetry system. DW-286a at 300 microM significantly (P<0.01) prolonged action potentials at 50% repolarization (APD50) and 90% repolarization (APD90). For IHERG, the IC50 value was 89.00+/-37.85 microM with a Hill coefficient (nH) of -0.97+/-0.49. However, when DW-286a was orally administered to conscious SD rats at a high dose (1000 mg/kg), no significant effect on ECG in vivo was detected. From a previous study, we know that concentration at 19.8 microM is the antimicrobial end-point of DW-286a. Therefore, our data suggest that in the electrophysiological aspect, it can be thought that the effective concentrations of DW-286a are between 19.8 and 100 microM (concentration in serum).
Kim
Eun-Joo
EJ
Department of Pharmacology and National Research Laboratory, Korea Institute of Toxicology, Yuseong, Daejeon, Korea. ejkim@kitox.re.kr
Kim
Ki-Suk
KS
Shin
Won-Ho
WH
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D009287:Naphthyridines / Q000009:adverse effects / Q000494:pharmacology*; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
C471029:7-(3-(aminomethyl)-4-(methoxyimino)-3-methyltetrahydro-1H-1-pyrrolyl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro(1,8)naphthyridine-3-carboxylic acid; D000900:Anti-Bacterial Agents; D051638:Ether-A-Go-Go Potassium Channels; D009287:Naphthyridines; D015221:Potassium Channels