QT PRODACT: In Vivo QT Assay in the Conscious Dog for Assessing the Potential for QT Interval Prolongation by Human Pharmaceuticals

DOI Web Site 被引用文献18件 参考文献87件
  • Toyoshima Shigeki
    Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan Division of Pharmacology, Drug Safety and Metabolism, Otsuka Pharmaceutical Factory, Inc., Japan
  • Kanno Akihiro
    Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan Pharmacological Research Laboratories, Drug Safety Testing Center Co., Ltd., Japan
  • Kitayama Tetsuya
    Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan Pharmaceutical Research Center Toxicological Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Japan
  • Sekiya Koji
    Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan Pharmacology & Toxicology Department, Ina Research, Inc., Japan
  • Nakai Keiko
    Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan Analysis and Metabolism Division, Kashima Laboratory, Mitsubishi Chemical Safety Institute Ltd., Japan
  • Haruna Masao
    Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan Developmental Research Laboratories, Shionogi & Co., Ltd., Japan
  • Mino Terumasa
    Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan Safety Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Japan
  • Miyazaki Hiroyasu
    Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan Tsukuba Safety Assessment Laboratories, Banyu Pharmaceutical Co., Ltd., Japan
  • Yano Koji
    Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan Drug Safety Research Laboratories, Tanabe Seiyaku Co., Ltd., Japan
  • Yamamoto Keiji
    Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan Development Research Center, Takeda Pharmaceutical Co., Ltd., Japan

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The goal of the present study was to examine the utility of the conscious dog model by assessing the QT-interval-prolonging potential of ten positive compounds that have been reported to induce QT interval prolongation in clinical use and seven negative compounds considered not to have such an effect. Three doses of test compounds or vehicle were administered orally to male beagle dogs (n = 4), and telemetry signals were recorded for 24 h after administration. All positive compounds (astemizole, bepridil, cisapride, E-4031, haloperidol, MK-499, pimozide, quinidine, terfenadine, and thioridazine) caused a significant increase in the corrected QT (QTc) interval, with a greater than 10% increase achieved at high doses. In contrast, administration of negative compounds (amoxicillin, captopril, ciprofloxacin, diphenhydramine, nifedipine, propranolol, and verapamil) did not produce any significant change in the QTc interval, with the exception of nifedipine that may have produced an overcorrection of the QTc interval due to increased heart rate. The estimated plasma concentrations of the positive compounds that caused a 10% increase in the QTc interval were in good agreement with the plasma/serum concentrations achieved in humans who developed prolonged QT interval or torsade de pointes (TdP). Although careful consideration should be given to the interpretation of QT data with marked heart rate change, these data suggest that an in vivo QT assay using the conscious dog is a useful model for the assessment of QT interval prolongation by human pharmaceuticals.<br> Supplementary material (Appendix): available only at http://dx.doi.org/10.1254/jphs.QT-A2<br>

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