Comparative pharmacodynamic analysis of Q-T interval prolongation induced by the macrolides clarithromycin, roxithromycin, and azithromycin in rats

In order to evaluate the arrhythmogenic potency of macrolide antibiotics in a quantitative manner, we analyzed the influence of clarithromycin (CAM), roxithromycin (RXM), and azithromycin (AZM) on Q-T intervals from pharmacok inetic and pharmacodynamic points of view and in comparison with the potenc y of erythromycin (EM) previously reported by us for rats. Male Sprague-Daw ley rats were anesthetized, and CAM (6.6, 21.6, and 43.2 mg/kg of body weig ht/h), RXM (20 and 40 mg/kg/h), and AZM (40 and 100 mg/kg/h) were intraveno usly injected for 90 min to obtain the time courses of drug concentrations in plasma and the changes in the Q-T intervals during and after the drug in jections. Distinct Q-T interval prolongation of up to 10 ms was observed wi th CAM at its clinical concentrations. RXM and AZM evoked Q-T interval prol ongation at concentrations higher than their clinical ranges. The potencies for Q-T interval prolongation, assessed as the slope of the concentration- response relationship, were 6.09, 0.536, and 0.989 ms . ml/mu g for CAM, RX M, and AZM, respectively. There was hysteresis between the change in the Q- T intervals and the time course of the plasma concentration of each drug. T he rank order of clinical arrhythmogenicity was estimated to be EM > CAM > RXM > AZM, as assessed from the present results and our previous report for EM. In conclusion, RXM and AZM were estimated to be less potent at provoki ng arrhythmia than EM and CAM. These results should be useful for making a safer choice of an appropriate agent for patients with electrocardiographic risk factors.