Key result
Erythromycin prolonged action potential duration and reduced delayed rectifier potassium current (IC50 = 60.1 μm) in rat ventricular myocytes, though its in-vitro potency was weaker than in-vivo.
Erythromycin prolongs action potential duration and inhibits delayed rectifier potassium currents in rat ventricular myocytes, providing a mechanistic basis for its QT-prolonging effects.
May explain erythromycin QT effects in rats; hypothesis-generating for human risk without clinical validation.
Disopyramide, a class la antiarrhythmic agent, has been reported to induce torsades de pointes (TdP) associated with excessive QT prolongation in electrocardiogram (ECG), especially when concomitantly administered with erythromycin, a macrolide antibiotic agent. In this study, we have evaluated the effects of erythromycin on action potential duration (APD) and potassium currents in rat ventricular myocytes in comparison with disopyramide. We have evaluated the relationship between in-vitro potassium current inhibition and in-vivo QT prolongation observed in a previous study. Action potentials and membrane potassium currents, including delayed rectifier current (IK) and transient outward current (Ito), were recorded using a whole-cell patch clamp method in enzymatically-dissociated ventricular cells. Erythromycin and disopyramide prolonged APD in a concentration-dependent manner. Disopyramide (10–100 μm) and erythromycin (100 μm) led to increases in the APD at 90% repolarization level. Disopyramide reduced IK (IC50 = 37.2 + 0.17 μm) and Ito (IC50 = 20.9 + 0.13 μm) while erythromycin reduced IK (IC50 = 60.1 + 0.29 μm) but not Ito. The observed prolongation of APD might be ascribed to the inhibition of potassium currents. Erythromycin produced the prolongation of APD and the inhibition of potassium currents with a lag time after addition of the drugs, which suggested that erythromycin might not reach potassium channels from outside the ventricular cells. The potency of disopyramide was almost equivalent under in-vitro and in-vivo conditions. However, potency of erythromycin in-vitro was far weaker than that in-vivo reported in a previous study, presumably due to a difference in the uptake of erythromycin into ventricular myocytes between in-vivo and in-vitro conditions. Therefore, when drug-induced risks of QT prolongation are to be evaluated, the difference of potencies between in-vitro and in-vivo should be taken into consideration.
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Hanada et al. (2003) studied this question. Erythromycin vs. Disopyramide was evaluated on Action potential duration and potassium currents. Erythromycin prolonged action potential duration and reduced delayed rectifier potassium current (IC50 = 60.1 μm) in rat ventricular myocytes, though its in-vitro potency was weaker than in-vivo.
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