Comparison of electropharmacological effects between terfenadine and its active derivative fexofenadine using a cross-over study in halothane-anesthetized dogs to analyze variability of pharmacodynamic and pharmacokinetic profiles of terfenadine and torsadogenic risk of fexofenadine

DOI Web Site Web Site PubMed 5 Citations 20 References Open Access
  • Ando Kentaro
    Department of Pharmacology, Faculty of Medicine, Toho University Department of Pharmacology, Toho University Graduate School of Medicine
  • Nakamura Yuji
    Department of Pharmacology, Faculty of Medicine, Toho University
  • Hagiwara-Nagasawa Mihoko
    Department of Pharmacology, Faculty of Medicine, Toho University
  • Harada Hiroyuki
    Mitsubishi Tanabe Pharma Corporation, Safety Research Laboratories, Sohyaku Innovative Research Division
  • Miyamoto Hiroyoshi
    Mitsubishi Tanabe Pharma Corporation, Safety Research Laboratories, Sohyaku Innovative Research Division
  • Inamura Naoki
    Mitsubishi Tanabe Pharma Corporation, Safety Research Laboratories, Sohyaku Innovative Research Division
  • Takagi Kan
    Mitsubishi Tanabe Pharma Corporation, Safety Research Laboratories, Sohyaku Innovative Research Division
  • Goto Ai
    Department of Pharmacology, Toho University Graduate School of Medicine
  • Chiba Koki
    Department of Pharmacology, Toho University Graduate School of Medicine
  • Lubna Nur Jaharat
    Department of Pharmacology, Toho University Graduate School of Medicine
  • Izumi-Nakaseko Hiroko
    Department of Pharmacology, Faculty of Medicine, Toho University
  • Naito Atsuhiko T.
    Department of Pharmacology, Faculty of Medicine, Toho University Department of Pharmacology, Toho University Graduate School of Medicine
  • Sugiyama Atsushi
    Department of Pharmacology, Faculty of Medicine, Toho University Department of Pharmacology, Toho University Graduate School of Medicine

Search this article

Abstract

<p>In order to better understand the variability of pharmacodynamic and pharmacokinetic profiles of terfenadine between the previous studies as well as to qualitatively and quantitatively examine the proarrhythmic potential of its major active metabolite fexofenadine in comparison with that of terfenadine, we directly compared their electropharmacological effects with halothane-anesthetized dogs (n = 3). For this purpose, we adopted a cross-over design, which can directly compare the effects of terfenadine and fexofenadine under the identical metabolic condition. Terfenadine in doses of 0.03 and 0.3 mg/kg increased the mean blood pressure, but that of 3 mg/kg decreased it. Terfenadine also increased the heart rate and ventricular contractility in a dose-related manner; but delayed the atrioventricular nodal and intraventricular conductions as well as repolarization suggesting its proarrhythmic potential. Meanwhile, fexofenadine in the same dose increased the mean blood pressure in a dose-related manner without affecting any of the electrophysiological variables in the same animals that proarrhythmic risk of terfenadine was confirmed, indicating its lack of proarrhythmic risk. Peak plasma concentrations for fexofenadine were 3.7, 8.1 and 11.2 times greater than for terfenadine at each matching dose, indicating terfenadine may be metabolized much faster than fexofenadine. Taken together, after the low and middle doses of terfenadine, vasopressor effect of a metabolite fexofenadine could be greater than the depressor effect of parent compound terfenadine, but its reverse would be correct after the high dose. Thus, the cross-over analysis can be an effective way to better understand drug-induced cardiovascular responses.</p>

Journal

Citations (5)*help

See more

References(20)*help

See more

Related Projects

See more

Keywords

Details 詳細情報について

Report a problem

Back to top