Pharmacokinetics, pharmacodynamics and toxicity of a combination of metoprolol succinate and telmisartan in Wistar albino rats: safety profiling.

Metoprolol succinate (MET), a cardioselective ß blocker and telmisartan (TEL), an angiotensin receptor blocker were administered orally, both individually and in combination to Wistar albino rats for evaluation of their pharmacokinetics, pharmacodynamics and repeated dose oral toxicity (28 days). Pharmacokinetic study was performed by analyzing drug concentration in plasma by a developed and validated LC-MS/MS method following oral administration of MET and TEL at 2.5 mg/kg and 2.0 mg/kg dose, respectively, both individually and in combination. Antihypertensive activity of MET and TEL in above dose and manner was evaluated on artificially induced hypertension on laboratory animals. In repeated dose oral toxicity study, MET (60, 120 and 240 mg/kg/day) and/or TEL (12, 24 and 48 mg/kg/day) were administered to animals for 28 days followed by a recovery period of 14 days. Pharmacokinetic data revealed the probable absence of any pharmacokinetic interaction when co-administered. Improved blood pressure lowering effect was observed by combination therapy. Moreover, toxic effects obtained at high dose level of each treatment groups were transient and reversible and no evidence of additive toxic effects were observed due to concomitant administration. So, this combination can primarily be stated as safe which will be confirmed after clinical interaction studies in humans.

Hypokalemia: a potent risk for QTc prolongation in clarithromycin treated rats.

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 10 mg/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 80 mg/kg for seven days. ECG was measured for 5 min in anaesthetised rat before and after 2 h 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 30 mg/kg) alone and in all the groups receiving clarithromycin alongside furosemide. Neither, clarithromycin (80 mg/kg) nor furosemide (10 mg/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.