Comparative evaluation of HERG currents and QT intervals following challenge with suspected torsadogenic and nontorsadogenic drugs

    Authors

    A. N. Katchman; J. Koerner; T. Tosaka; R. L. Woosley;S. N. Ebert

    Comments

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    Abbreviated Journal Title

    J. Pharmacol. Exp. Ther.

    Keywords

    TORSADES-DE-POINTES; PNEUMOCYSTIS-CARINII PNEUMONIA; ISOLATED RABBIT; HEART; ARSENIC TRIOXIDE; VENTRICULAR-TACHYCARDIA; CARDIAC; REPOLARIZATION; PENTAMIDINE THERAPY; POTASSIUM CURRENTS; FEMALE GENDER; K+ CHANNELS; Pharmacology & Pharmacy

    Abstract

    The purpose of the present study was to comparatively evaluate human HERG currents and QT intervals following challenge with suspected torsadogenic and nontorsadogenic drugs. Various concentrations of 14 different drugs were initially evaluated in terms of their relative potency to block I HERG in stably transfected human embryonic kidney cells. Four general categories of drugs were identified: high-potency blockers ( IC50 < 0.1 mu M) included lidoflazine, terfenadine, and haloperidol; moderate-potency blockers ( 0.1 mu M < IC50 < 1 mu M) included sertindole, thioridazine, and prenylamine; low-potency blockers ( IC50 > 1 mu M) included propafenone, loratadine, pyrilamine, lovastatin, and chlorpheniramine; and ineffective blockers ( IC50 > 300 mu M) included cimetidine, pentamidine, and arsenic trioxide. All measurements were performed using similar conditions and tested acute drug effects only ( < 30 min of drug exposure per measurement). Since two of the drugs that were ineffective I HERG 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 I-HERG.

    Journal Title

    Journal of Pharmacology and Experimental Therapeutics

    Volume

    316

    Issue/Number

    3

    Publication Date

    1-1-2006

    Document Type

    Article

    Language

    English

    First Page

    1098

    Last Page

    1106

    WOS Identifier

    WOS:000235476000016

    ISSN

    0022-3565

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