The Effect of Increased Free Concentrations of Warfarin Due to Protein-binding Substitution in a Combination of Tolvaptan on the PT-INR

  • Saito Masayuki
    Department of Pharmacy, Tosei General Hospital Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University
  • Maeda Tohru
    College of Pharmacy, Kinjo Gakuin University
  • Ichihara Toshihiko
    Department of Emergency Medicine, Tosei General Hospital
  • Iwao Takahiro
    Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University
  • Suzuki Tadashi
    Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University

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Abstract

<p>We previously reported that tolvaptan may influence warfarin pharmacodynamics in vivo; however, the mechanism responsible for this influence was not clear. In this study, we investigated the drug-drug interactions between warfarin and tolvaptan by measuring warfarin blood concentrations in 18 patients who received warfarin therapy and in 24 who received warfarin+tolvaptan therapy. The free warfarin concentrations significantly increased in patients who were also receiving oral tolvaptan (p=0.04). In vitro albumin-binding experiments showed that the free warfarin concentrations significantly increased with the addition of tolvaptan, in a dose-dependent manner, through albumin-binding substitution (approximately 2.5 times). Both clinical and in vitro data showed that tolvaptan increased the unbound warfarin serum concentration. The prothrombin time-international normalized ratio (PT-INR) tended to increase within 2 weeks when tolvaptan was added at clinically used doses (p=0.14). Special attention is warranted in cases with a serum tolvaptan concentration of ≥125 ng/mL (≥7.5 mg/d) for at least 2 weeks following oral tolvaptan administration.</p>

Journal

  • YAKUGAKU ZASSHI

    YAKUGAKU ZASSHI 140 (10), 1269-1274, 2020-10-01

    The Pharmaceutical Society of Japan

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