title: The action of a novel fluoroquinolone antibiotic agent antofloxacin hydrochloride on human-ether-à-go-go-related gene potassium channel.
abstract: 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.
authors.affiliation: College of Life Science, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Nanjing Normal University, Nanjing, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Guo
authors.forename: Sheng-Na
authors.initials: SN
authors.lastname: Han
authors.forename: Jin-Xu
authors.initials: JX
authors.lastname: Liu
authors.forename: Xiang-Mei
authors.initials: XM
authors.lastname: Zhang
authors.forename: Zhen-Sheng
authors.initials: ZS
authors.lastname: Hu
authors.forename: Jie
authors.initials: J
authors.lastname: Shi
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Zhang
authors.forename: Zhong-Zhong
authors.initials: ZZ
authors.lastname: Zhao
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhang
mesh_terms: 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
chemical_list: 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