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The utility of hERG and repolarization assays in evaluating delayed cardiac repolarization: influence of

Ruth L Martin1, Jeff S McDermott, Heinz J Salmen

  • 1Department of Integrative Pharmacology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6119, USA.

Journal of Cardiovascular Pharmacology
|April 13, 2004
PubMed

Insights

Drug block of the hERG channel can prolong cardiac repolarization, increasing arrhythmia risk. However, hERG assays alone may oversimplify drug effects, as multi-channel block can alter outcomes.

Area of Science:

  • Cardiovascular pharmacology
  • Electrophysiology
  • Drug safety assessment

Background:

  • Drug-induced delayed cardiac repolarization is a risk factor for proarrhythmia.
  • This is often linked to block of the IKr (hERG) potassium current.
  • In vitro assays are used to predict these cardiac effects.

Purpose of the Study:

  • To evaluate the utility of hERG and canine Purkinje fiber action potential duration (APD) assays.
  • To compare drug effects on repolarization and hERG channel block.
  • To assess the predictive value of these assays for proarrhythmic risk.

Main Methods:

  • Tested haloperidol and 9 diverse drugs across wide concentration ranges.
  • Utilized hERG current assays and canine Purkinje fiber APD assays.
  • Investigated effects of nifedipine and lidocaine on dofetilide-induced APD prolongation.

Main Results:

  • Haloperidol showed bell-shaped APD prolongation despite potent hERG block, suggesting multi-channel effects.
  • APD prolongation by dofetilide was modulated by calcium and sodium channel blockers.
  • Most drugs (9/10) inhibited hERG significantly, but APD changes varied widely, indicating multi-channel block.

Conclusions:

  • The hERG assay may oversimplify drug effects on cardiac repolarization, especially with multi-channel block.
  • Neither the hERG assay nor the APD assay alone adequately predicts proarrhythmic risk.
  • Assessing multi-channel interactions is crucial for accurate drug safety evaluation.

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