Hypokalemia: A potent risk for QTc prolongation in clarithromycin treated rats

Abstract

Clarithromycin belongs to macrolide group of antibiotics commonly known for their proarrhythmic potency. Besides agents interfering with CYP 3A, electrolyte imbalance might influence repolarization problems of clarithromycin. The proarrhythmic tendency of clarithromycin particularly in association with hypokalemia manifested a change in QT interval in rat electrocardiogram (ECG). Varying degree of hypokalemia was induced by intraperitoneal injection of furosemide (50, 30, and 10mg/kg, for seven days). The serum electrolyte levels confirmed that hypokalemia was established in the groups receiving furosemide. Simultaneously, clarithromycin was orally administered in the doses of 100 and 80mg/kg for seven days. ECG was measured for 5min in anaesthetised rat before and after 2h of treatment. The QT interval was corrected for heart rate and reported as corrected QT (QTc). Distinct QTc interval prolongation was observed in groups receiving furosemide (50 and 30mg/kg) alone and in all the groups receiving clarithromycin alongside furosemide. Neither, clarithromycin (80mg/kg) nor furosemide (10mg/kg) exhibited any significant change in the QTc interval but in combination these drugs led to a significant increase in the QTc interval. Most interestingly, potassium supplementation was found to reduce QTc interval in the group presenting with maximum QTc prolongation. These results suggest that hypokalemic condition potentiates the clarithromycin induced QTc prolongation, thereby indicating the importance of monitoring serum electrolyte during clarithromycin therapy. Although, selection of rat for examination of proarrhythmic liability is controversial, this report may be considered as an evidence of hypokalemia potentiating clarithromycin induced QTc prolongation.