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Electrophysiological safety of DW-286a, a novel fluoroquinolone antibiotic agent

Department of Pharmacology and National Research Laboratory, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, Korea; Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Yuseong, Daejeon 305-343, Korea ejkim{at}kitox.re.kr

Ki-Suk Kim

Won-Ho Shin

Department of Pharmacology and National Research Laboratory, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, Korea

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-á-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 µM significantly (P <0.01) prolonged action potentials at 50% repolarization (APD₅₀) and 90% repolarization (APD₉₀). For I _HERG, the IC₅₀ value was 89.00±37.85 µM with a Hill coefficient (n ^H) 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 µM 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 µM (concentration in serum).

Key Words: DW-286a • Fluoroquinolone • human ether-á-go-go related gene (hERG) • QT prolongation • patch clamp techniques

Human & Experimental Toxicology, Vol. 24, No. 1, 19-25 (2005)
DOI: 10.1191/0960327105ht494oa


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