The macrolide drug erythromycin does not protect the hERG channel from inhibition by thioridazine and terfenadine

The macrolide antibiotic erythromycin has been associated with QT interval prolongation and inhibition of the hERG‐encoded channels responsible for the rapid delayed rectifier K(+) current I((Kr)). It has been suggested that low concentrations of erythromycin may have a protective effect against hERG block and associated drug‐induced arrhythmia by reducing the affinity of the pore‐binding site for high potency hERG inhibitors. This study aimed to explore further the notion of a potentially protective effect of erythromycin. Whole‐cell patch‐clamp experiments were performed in which hERG‐expressing mammalian (Human Embryonic Kidney; HEK) cells were preincubated with low to moderate concentrations of erythromycin (3 or 30 µM) prior to whole‐cell patch clamp recordings of hERG current (I(hERG)) at 37°C. In contrast to a previous report, exposure to low concentrations of erythromycin did not reduce pharmacological sensitivity of hERG to the antipsychotic thioridazine and antihistamine terfenadine. The IC(50) value for I(hERG) tail inhibition by terfenadine was decreased by ~32‐fold in the presence of 3 µM erythromycin (p < .05 vs. no preincubation). Sensitivity to thioridazine remained unchanged (p > .05 vs. no preincubation). The effects of low concentrations of erythromycin were investigated for a series of pore blocking drugs, and the results obtained were consistent with additive and/or synergistic effects. Experiments with the externally acting blocker BeKm‐1 on WT hERG and a pore mutant (F656V) were used to explore the location of the binding site for erythromycin. Our data are inconsistent with the use of erythromycin for the management of drug‐induced QT prolongation.