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

Hum Exp Toxicol. 2005 Jan;24(1):19-25. doi: 10.1191/0960327105ht494oa.

Abstract

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-à-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 microM significantly (P<0.01) prolonged action potentials at 50% repolarization (APD50) and 90% repolarization (APD90). For IHERG, the IC50 value was 89.00+/-37.85 microM with a Hill coefficient (nH) 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 microM 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 microM (concentration in serum).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects*
  • Animals
  • Anti-Bacterial Agents / adverse effects
  • Anti-Bacterial Agents / pharmacology*
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Dogs
  • Electrophysiology*
  • Ether-A-Go-Go Potassium Channels
  • Guinea Pigs
  • Heart Rate / drug effects
  • Humans
  • Male
  • Naphthyridines / adverse effects
  • Naphthyridines / pharmacology*
  • Papillary Muscles / drug effects
  • Papillary Muscles / physiology
  • Patch-Clamp Techniques
  • Potassium Channels / drug effects*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • 7-(3-(aminomethyl)-4-(methoxyimino)-3-methyltetrahydro-1H-1-pyrrolyl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro(1,8)naphthyridine-3-carboxylic acid
  • Anti-Bacterial Agents
  • Ether-A-Go-Go Potassium Channels
  • Naphthyridines
  • Potassium Channels