Temperature variation altered hERG channel blockade, with amiodarone and β-estradiol showing higher blockade at 37 °C, whereas ivermectin and frusemide showed lower blockade at 37 °C.
Does temperature variation affect the hERG channel blockade potential of various drugs in vitro?
Temperature variation significantly alters the hERG channel blockade potential of certain drugs, highlighting the importance of testing at physiological temperatures during drug safety evaluation.
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 (IKr) 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 IKr inhibition at both ambient (23 °C) and physiological (37 °C) temperatures at various concentrations using IonFlux 16, an automated patch clamp system. Our results established that both amiodarone (IC(50) = 0.56 μM at 23 °C and 0.30 μM at 37 °C) and β-estradiol (IC(50) = 24.72 μM at 23 °C and 8.17 μM at 37 °C) showed a dose-dependent IKr blockade with a higher blockade at 37 °C. Whereas, blockade of IKr by both ivermectin (IC(50) = 12.52 μM at 23 °C and 24.41 μM at 37 °C) and frusemide (IC(50) = 12.58 μM at 23 °C and 25.55 μM at 37 °C) showed a dose-dependent IKr blockade with a lower blockade at 37 °C. Gentamicin, enrofloxacin, xylazine and albendazole did not block IKr 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.
Kauthale et al. (2014) studied Drug-induced QT prolongation. Physiological temperature (37 °C) vs. Ambient temperature (23 °C) was evaluated on IKr inhibition (IC50). Temperature variation altered hERG channel blockade, with amiodarone and β-estradiol showing higher blockade at 37 °C, whereas ivermectin and frusemide showed lower blockade at 37 °C.