The action of a novel fluoroquinolone antibiotic agent antofloxacin hydrochloride on human-ether-à-go-go-related gene potassium channel

Basic Clin Pharmacol Toxicol. 2010 Aug;107(2):643-9. doi: 10.1111/j.1742-7843.2010.00550.x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Cell Line
  • Dose-Response Relationship, Drug
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / drug effects*
  • Ether-A-Go-Go Potassium Channels / genetics
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Fluoroquinolones / pharmacology
  • Gene Expression Regulation / drug effects*
  • Humans
  • Kidney / cytology
  • Kidney / embryology
  • Levofloxacin*
  • Ofloxacin / analogs & derivatives*
  • Ofloxacin / pharmacology
  • Patch-Clamp Techniques
  • Potassium Channel Blockers / pharmacology*
  • Potassium Channels, Voltage-Gated / drug effects*
  • Protein Transport
  • Structure-Activity Relationship
  • Transfection

Substances

  • Anti-Bacterial Agents
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • Fluoroquinolones
  • KCNH2 protein, human
  • Potassium Channel Blockers
  • Potassium Channels, Voltage-Gated
  • antofloxacin
  • Levofloxacin
  • Ofloxacin
  • sparfloxacin