Assessment of temperature-induced hERG channel blockade variation by drugs

Drug-induced QT prolongation has been reported in humans and animals. This potentially lethal effect can be induced by drugs interacting with a cardiac potassium channel, namely hERG (human ether-a go-go-related gene) leading to arrhythmia or torsade de pointes (TdP). Hence, in vitro evaluation of therapeutics for their effects on the rapid delayed rectifier current (I-Kr) mediated by the K+ ion channel encoded by hERG is a valuable tool for identifying potential arrhythmic side effects during drug safety testing. Our objective was to evaluate the temperature-induced hERG channel blockade variation by human and veterinary drugs using the IonFlux 16 system. A panel of eight drugs was tested for I-Kr inhibition at both ambient (23 degrees C) and physiological (37 degrees C) temperatures at various concentrations using IonFlux 16, an automated patch clamp system. Our results established that both amiodarone (IC50=0.56M at 23 degrees C and 0.30M at 37 degrees C) and -estradiol (IC50=24.72M at 23 degrees C and 8.17M at 37 degrees C) showed a dose-dependent I-Kr blockade with a higher blockade at 37 degrees C. Whereas, blockade of I-Kr by both ivermectin (IC50=12.52M at 23 degrees C and 24.41M at 37 degrees C) and frusemide (IC50=12.58M at 23 degrees C and 25.55M at 37 degrees C) showed a dose-dependent I-Kr blockade with a lower blockade at 37 degrees C. Gentamicin, enrofloxacin, xylazine and albendazole did not block I-Kr at both the assessed temperatures. Collectively, these results demonstrate that the effect of temperature variation should be taken into consideration during the evaluation of test drugs for their hERG channel blockade potential. Copyright (c) 2014 John Wiley & Sons, Ltd.