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

Abstract

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 pharmacokinetic and pharmacodynamic points of view and in comparison with the potency of erythromycin (EM) previously reported by us for rats. Male Sprague-Dawley rats were anesthetized, and CAM (6.6, 21.6, and 43.2 mg/kg of body weight/h), RXM (20 and 40 mg/kg/h), and AZM (40 and 100 mg/kg/h) were intravenously 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 injections. Distinct Q-T interval prolongation of up to 10 ms was observed with CAM at its clinical concentrations. RXM and AZM evoked Q-T interval prolongation 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/microg for CAM, RXM, 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. The 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 provoking 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.

FIG. 1

Typical change in ECG shapes evoked by a constant intravenous infusion of CAM (21.6 mg/kg/h). The ECG shapes before and 30 and 90 min after the beginning of CAM infusion are shown in a superimposed manner.

FIG. 2

Changes in Q-T intervals before and after intravenous infusion of CAM (■, 6.6 mg/kg/h [n = 5]; ▴, 21.6 mg/kg/h [n = 6]; ●, 43.2 mg/kg/h [n = 6]) (A), RXM (▴, 20 mg/kg/h [n = 5]; ●, 40 mg/kg/h [n = 5]) (B), and AZM (▴, 40 mg/kg/h [n = 5]; ●, 100 mg/kg/h [n = 5]) (C) compared with data previously reported by us (9) for EM (○, vehicle [n = 5]; ▴, 4.0 mg/kg/h [n = 5]; ●, 8.0 mg/kg/h [n = 4]) (D). Data are reported as mean and standard error of the mean.

FIG. 3

Time courses of the concentrations in plasma of CAM (■, 6.6 mg/kg/h [n = 3]; ▴, 21.6 mg/kg/h [n = 3]; ●, 43.2 mg/kg/h [n = 3]) (A), RXM (▴, 20 mg/kg/h [n = 4]; ●, 40 mg/kg/h [n = 3]) (B), and AZM (▴, 40 mg/kg/h [n = 3]; ●, 100 mg/kg/h [n = 3]) (C) compared with data previously reported by us (9) for EM (▴, 4.0 mg/kg/h [n = 4]; ●, 8.0 mg/kg/h [n = 4]) (D). Data are reported as mean and standard error of the mean.

FIG. 4

Relationships between drug concentrations in plasma and changes in Q-T interval (n = 5 or 6) for CAM (A), RXM (B), AZM (C), and EM (9) (D). Each arrow indicates the ECG recording time. Data are reported as mean and standard error of the mean. Symbols are the same as for Fig. 2 and 3.

FIG. 5

Relationships between drug concentrations in the effect compartment and changes in Q-T interval (n = 5 or 6). The lines calculated from equations 1 or 2 are superimposed. (A) CAM. (B) RXM. (C) AZM. (D) EM. (9). Data are reported as mean and standard error of the mean. Symbols are the same as for Fig. 2 and 3.

FIG. 6

Estimated ranges for Q-T interval prolongation evoked in rats by macrolides at clinical plasma drug concentration ranges.