The action of a novel fluoroquinolone antibiotic agent antofloxacin hydrochloride on human-ether-à-go-go-related gene potassium channel.
The administration of certain fluoroquinolone antibacterials has recently been linked to QT interval prolongation, raising the clinical concerns over the cardiotoxicity of these agents. In this study, the effects of a novel fluoroquinolone, antofloxacin hydrochloride (AX) on human-ether-à-go-go-related gene (HERG) encoding potassium channels and the biophysical mechanisms of drug action were performed with whole-cell patch-clamp technique in transiently transfected HEK293 cells. The administration of AX caused voltage- and time-dependent inhibition of HERG K+ current (I(HERG/MiRP1)) in a concentration-dependent manner but did not markedly modify the properties of channel kinetics, including activation, inactivation, deactivation and recovery from inactivation as well. In comparison with sparfloxacin (SPX), levofloxacin lactate (LVFX), the potency of AX to inhibit HERG tail currents was the least one, with an IC(50) value of 460.37 microM. By contrast, SPX was the most potent compound, displaying an IC(50) value of 2.69 microM whereas LVFX showed modest potency, with an IC(50) value of 43.86 microM, respectively. Taken together, our data suggest that AX only causes a minor reduction of I(HERG/MiRP1) at the estimated free plasma level.
Guo
Jia
J
College of Life Science, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Nanjing Normal University, Nanjing, China.
Han
Sheng-Na
SN
Liu
Jin-Xu
JX
Zhang
Xiang-Mei
XM
Hu
Zhen-Sheng
ZS
Shi
Jie
J
Zhang
Li-Rong
LR
Zhao
Zhong-Zhong
ZZ
Zhang
Zhao
Z
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D024841:Fluoroquinolones / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000196:embryology; D064704:Levofloxacin; D015242:Ofloxacin / Q000031:analogs & derivatives* / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects*; D021381:Protein Transport; D013329:Structure-Activity Relationship; D014162:Transfection
D000900:Anti-Bacterial Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D024841:Fluoroquinolones; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; C522674:antofloxacin; D064704:Levofloxacin; D015242:Ofloxacin; C061363:sparfloxacin