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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 8, 2005; DOI: 10.1124/jpet.105.093393

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Received for publication July 28, 2005.
Revised November 3, 2005.
Accepted for publication November 7, 2005.

Comparative Evaluation of HERG Currents and QT Intervals following Challenge with Suspected Torsadogenic and Non-Torsadogenic Drugs

Alexander N Katchman 1, John Koerner 2, Toshimasa Tosaka 1, Raymond L Woosley 3, Steven N Ebert 4*

1 Georgetown University Medical Center 2 United States Food and Drug Administration 3 The C-Path Institute 4 University of Central Florida

* Address correspondence to: E-mail: ebert{at}mail.ucf.edu

Abstract

The purpose of the present study was to comparatively evaluate HERG currents and QT intervals following challenge with suspected torsadogenic and non-torsadogenic drugs. Various concentrations of 14 different drugs were initially evaluated in terms of their relative potency to block IHERG in stably-transfected HEK cells. Four general categories of drugs were identified: (1) High-potency blockers (IC50 < 0.1 µM) included lidoflazine, terfenadine, and haloperidol; (2) Moderate-potency blockers (0.1 µM < IC50 < 1 µM) included sertindole, thioridazine, and prenylamine; (3) Low-potency blockers (IC50 > 1 µM) included propafenone, loratadine, pyrilamine, lovastatin, and chlorpheniramine; and (4) Ineffective blockers (IC50 > 300 µM) included cimetidine, pentamidine, and arsenic trioxide. All evaluations were performed using similar conditions and tested acute drug effects only (< 30 mins of drug exposure per measurement). Since two of the drugs that were ineffective IHERG blockers, arsenic trioxide and pentamidine, have been associated with cardiac repolarization delays (QT interval lengthening) and torsades de pointes ventricular arrhythmias in patients, we chose to evaluate them further using the isolated perfused rabbit heart model. Neither arsenic trioxide nor pentamidine had any significant effect on QT intervals in this model, even at relatively high (micromolar) concentrations. Similar results were obtained for loratadine in this model. When the hearts were challenged with a known torsadogenic drug such as cisapride, significant QT-lengthening was rapidly induced. These results demonstrate that arsenic trioxide and pentamidine are essentially devoid of direct acute effects on cardiac repolarization or inhibition of IHERG.


Key words: Arrhythmia, ECG, FDA, HEK cells, Potassium channels, Rabbit


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