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Pharmacokinetic–pharmacodynamic analysis of the arrhythmogenic potency of a novel antiallergic agent, ebastine, in rats
Author(s) -
Ohtani Hisakazu,
Sato Hitoshi,
Iga Tatsuji,
Kotaki Hajime,
Sawada Yasufumi
Publication year - 1999
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/(sici)1099-081x(199903)20:2<101::aid-bdd160>3.0.co;2-l
Subject(s) - terfenadine , pharmacology , potency , pharmacodynamics , pharmacokinetics , chemistry , astemizole , metabolite , qt interval , herg , ec50 , active metabolite , medicine , anesthesia , potassium channel , in vitro , biochemistry
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 EC 50 , E max and EC 10 ms (where 10 ms of QT prolongation was evoked) of 0.73 μg/mL, 12.5 ms and 2.90 μg/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. Copyright © 1999 John Wiley & Sons, Ltd.