Pharmacokinetic-pharmacodynamic analysis of the arrhythmogenic potency of a novel antiallergic agent, ebastine, in rats.
Ebastine (EBS), a novel nonsedative antiallergic agent, is similar to terfenadine in its chemical structure. However, clinical arrhythmogenicity of EBS remains controversial. In this study, we evaluated the possible arrhythmogenic potency of EBS as assessed by QT prolongation from a pharmacokinetic-pharmacodynamic viewpoint in comparison with that of terfenadine. EBS was intravenously infused into anesthetized rats at a rate of 3.0 or 10 mg/kg/h for 60 min, and electrocardiographic effects were continuously monitored from lead II. The plasma concentrations of EBS and its major metabolite, carebastine, were also measured under the same conditions. When intravenously administered, EBS exhibited QT prolongation in an infusion rate-dependent manner, with a lag time. Pharmacokinetic-pharmacodynamic analysis of EBS based on the effect-compartment model revealed values of EC50, Emax and EC(10 ms), (where 10 ms of QT prolongation was evoked) of 0.73 microg/mL, 12.5 ms and 2.90 microg/mL, respectively. The EC(10 ms) value of EBS was five times higher than that of terfenadine reported previously (Ohtani et al., J. Pharm. Pharmacol., 49, 458-462 (1997)). In conclusion, EBS was suggested to be less arrhythmogenic than terfenadine.
Ohtani
H
H
Department of Pharmacy, University of Tokyo Hospital, The University of Tokyo, Japan.
Sato
H
H
Iga
T
T
Kotaki
H
H
Sawada
Y
Y
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D002090:Butyrophenones / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D004562:Electrocardiography / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D008297:Male; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016593:Terfenadine / Q000493:pharmacokinetics / Q000633:toxicity
D002090:Butyrophenones; D006634:Histamine H1 Antagonists; D010880:Piperidines; C058251:carebastine; D016593:Terfenadine; C058249:ebastine