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Antimicrobial Agents and Chemotherapy, October 2000, p. 2630-2637, Vol. 44, No. 10
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Comparative Pharmacodynamic Analysis of Q-T Interval Prolongation Induced by the Macrolides Clarithromycin, Roxithromycin, and Azithromycin in Rats

Hisakazu Ohtani,1,* Chieko Taninaka,1 Erika Hanada,1 Hajime Kotaki,1,dagger Hitoshi Sato,1,Dagger Yasufumi Sawada,2 and Tatsuji Iga1

Department of Pharmacy, University of Tokyo Hospital, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655,1 and Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Fukuoka 812-8582,2 Japan

Received 30 December 1999/Returned for modification 29 April 2000/Accepted 21 June 2000

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/µg 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.

* Corresponding author. Present address: Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Fukuoka 812-8582, Japan. Phone: 81-92-642-6613. Fax: 81-92-642-6614. E-mail: ohtani-tky{at}umin.ac.jp.

dagger Present address: Institute of Medical Sciences, University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

Dagger Present address: Department of Clinical and Molecular Pharmacology/Pharmacodynamics, School of Pharmaceutical Sciences, Showa University, Shinagawa-ku, Tokyo 142-8555, Japan.

Antimicrobial Agents and Chemotherapy, October 2000, p. 2630-2637, Vol. 44, No. 10
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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