PT - JOURNAL ARTICLE AU - Alexander N. Katchman AU - John Koerner AU - Toshimasa Tosaka AU - Raymond L. Woosley AU - Steven N. Ebert TI - Comparative Evaluation of <em>HERG</em> Currents and QT Intervals following Challenge with Suspected Torsadogenic and Nontorsadogenic Drugs AID - 10.1124/jpet.105.093393 DP - 2006 Mar 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1098--1106 VI - 316 IP - 3 4099 - http://jpet.aspetjournals.org/content/316/3/1098.short 4100 - http://jpet.aspetjournals.org/content/316/3/1098.full SO - J Pharmacol Exp Ther2006 Mar 01; 316 AB - 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 IHERG in stably transfected human embryonic kidney cells. Four general categories of drugs were identified: high-potency blockers (IC50 &lt; 0.1 μM) included lidoflazine, terfenadine, and haloperidol; moderate-potency blockers (0.1 μM &lt; IC50 &lt; 1 μM) included sertindole, thioridazine, and prenylamine; low-potency blockers (IC50 &gt; 1 μM) included propafenone, loratadine, pyrilamine, lovastatin, and chlorpheniramine; and ineffective blockers (IC50 &gt; 300 μM) included cimetidine, pentamidine, and arsenic trioxide. All measurements were performed using similar conditions and tested acute drug effects only (&lt;30 min 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.