Allosteric effects of erythromycin pretreatment on thioridazine block of hERG potassium channels.

BACKGROUND AND PURPOSE: The prevalence of concurrent use of two or more drugs that block human ether-a-go-go-related gene product (hERG) K(+) channels is not uncommon, but is not well characterized. This study defined the effects of concurrent exposure of two hERG-blocking drugs on hERG current amplitude. Experiments were conducted to determine if concomitant exposure to two potent pore hERG blockers, thioridazine and terfenadine and a weak hERG blocker, erythromycin, would result in an additive, synergistic or inhibitory effect.

EXPERIMENTAL APPROACH: hERG currents from stably transfected HEK cells were measured using the whole-cell variant of the patch-clamp method at physiological temperatures. Concentration-response relationships for thioridazine or terfenadine were obtained with cells pre-exposed to erythromycin.

KEY RESULTS: Pre-exposure of cells to erythromycin resulted in an approximately 14-22-fold rightward shift in the hERG concentration-response curve for thioridazine and terfenadine respectively. This reduction in affinity was not the result of a change in the voltage-dependent characteristics of the channel. Results suggest an external binding site for erythromycin.

CONCLUSIONS AND IMPLICATIONS: Pretreatment with erythromycin induced an approximately 14-22-fold reduction in hERG affinity for pore-binding drugs at concentrations of erythromycin, which by themselves only block hERG by 10% or less. These results suggest distinct, allosterically linked binding sites on opposite sides of the hERG channel. Occupancy of the external site by erythromycin reduces the affinity of the pore binding site. Furthermore, these results suggest that co-administration of erythromycin may provide some reduction in cardiac liability of potent hERG-blocking drugs.