Safety pharmacology of DW-224a, a novel fluoroquinolone antibiotic agent.
To investigate the safety pharmacology of a novel fluoroquinolone antibiotic agent, DW-224a, on the vital functions, we studied its effects on the central nervous system, cardiovascular system and respiratory system. To determine the effects on the central nervous system, we used a modified Irwin's test at each time point after oral administration of DW-224a to mice. In this test, we found that the treatment of test article had no effects on motor activity, behavioral changes, coordination, and sensory/motor reflex responses. The effects of DW-224a on the cardiovascular system were evaluated by the use of a telemetry system in beagle dogs. At 360 min post-DW-224a (100 mg/kg) administration, QT interval prolongation was observed. However, there were no changes in heart rate, blood pressure, and electrocardiogram at all doses and each time points with the exception of QT-interval prolongation as compared to the vehicle treated group. In experiments designed to determine the changes of respiratory function in rats, we found no changes at all doses and time points. We investigated the effects of DW-224a on the human ether-a-go-go-related gene (hERG) mediated potassium currents to evaluate its potential to induce QT interval prolongation. When whole cell patch-clamp electrophysiology was used, DW-224a inhibited hERG currents with IC50 of 218.12 +/- 39.51 microM though its effect was less potent than that of E-4031, a positive control drug. Our data suggested that DW-224a showed no adverse effects on the central nervous system, cardiovascular system, and respiratory system, with the exception of the effect on the QT interval prolongation.
Kim
Eun-Joo
EJ
Department of Pharmacology and National Research Laboratory, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, South Korea. ejkim@kitox.re.kr
Shin
Won-Ho
WH
Kim
Ki-Suk
KS
Han
Sang-Seop
SS
D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D001522:Behavior, Animal / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D004285:Dogs; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D024841:Fluoroquinolones / Q000633:toxicity*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley
D000900:Anti-Bacterial Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D024841:Fluoroquinolones; C000606913:KCNH2 protein, human; D024642:Potassium Channels, Voltage-Gated; C480202:zabofloxacin