Blockade of human cardiac potassium channel human ether-a-go-go-related gene (HERG) by macrolide antibiotics

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Walter A Volberg1, Bryan J Koci, Weiguo Su

  • 1Department of General Pharmacology, Groton Laboratories, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.

The Journal of Pharmacology and Experimental Therapeutics
|June 18, 2002
PubMed

Insights

Several macrolide antibiotics can prolong the QT interval. This study found that macrolides inhibit the human ether-a-go-go-related gene (HERG) potassium channel, potentially explaining their cardiac risks.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Cardiology

Background:

  • Macrolide antibiotics are associated with QT prolongation and potentially fatal ventricular arrhythmias.
  • The precise ionic mechanisms underlying these cardiac side effects remain incompletely understood.

Purpose of the Study:

  • To investigate the effects of six macrolides on the human ether-a-go-go-related gene (HERG) potassium current.
  • To elucidate the ionic mechanisms by which macrolides may induce QT prolongation.

Main Methods:

  • Stable expression of HERG channels in human embryonic kidney-293 cells.
  • Electrophysiological recordings to assess HERG current inhibition by macrolides.
  • Concentration-dependent inhibition assays and mechanistic studies (voltage/time-dependence).

Main Results:

  • All six tested macrolides (clarithromycin, roxithromycin, erythromycin, josamycin, erythromycylamine, oleandomycin) inhibited HERG current in a concentration-dependent manner.
  • IC(50) values ranged from 32.9 microM (clarithromycin) to 339.6 microM (oleandomycin).
  • A metabolite of erythromycin also inhibited HERG current. Clarithromycin's inhibition was voltage- and time-dependent, suggesting a direct channel blockade.

Conclusions:

  • HERG channel blockade is a common feature among macrolides.
  • This HERG channel inhibition may contribute to the clinical observation of QT prolongation associated with macrolide use.
  • The drug-channel interaction is influenced by membrane potential, indicating electrostatic effects in the blocking mechanism.

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