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Comparative pharmacodynamic analysis of Q-T interval prolongation induced by the macrolides clarithromycin,
H Ohtani1, C Taninaka, E Hanada
1Department of Pharmacy, University of Tokyo Hospital, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. ohtani-tky@umin.ac.jp
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.
Insights
Clarithromycin (CAM) can prolong Q-T intervals at clinical concentrations, while roxithromycin (RXM) and azithromycin (AZM) require higher doses. The rank order for arrhythmogenic potency is erythromycin (EM) > CAM > RXM > AZM.
Area of Science:
- Pharmacology
- Cardiology
- Drug Safety
Background:
- Macrolide antibiotics can cause Q-T interval prolongation, a risk factor for cardiac arrhythmias.
- Quantitative assessment of arrhythmogenic potency is crucial for patient safety.
Purpose of the Study:
- To quantitatively evaluate the arrhythmogenic potency of clarithromycin (CAM), roxithromycin (RXM), and azithromycin (AZM).
- To compare their Q-T interval prolonging effects with erythromycin (EM).
Main Methods:
- Intravenous administration of CAM, RXM, and AZM to anesthetized male Sprague-Dawley rats.
- Monitoring of plasma drug concentrations and Q-T intervals over time.
- Pharmacokinetic and pharmacodynamic analysis to determine concentration-response relationships.
Main Results:
- Clarithromycin (CAM) caused Q-T prolongation up to 10 ms at clinical concentrations.
- Roxithromycin (RXM) and azithromycin (AZM) induced Q-T prolongation at supra-clinical concentrations.
- Potency ranking for Q-T prolongation: CAM (6.09) > AZM (0.989) > RXM (0.536) ms·ml/µg.
- Estimated clinical arrhythmogenicity rank: EM > CAM > RXM > AZM.
Conclusions:
- RXM and AZM exhibit lower arrhythmogenic potency compared to EM and CAM.
- These findings aid in selecting safer macrolides for patients with electrocardiographic risk factors.