Characteristics of Gastrointestinal Absorption of DX-9065a, a New Synthetic Anticoagulant

• FUJII Yoshimine

  Drug Metabolism & Physicochemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd.

• TAKAHASHI Masayuki

  Drug Metabolism & Physicochemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd.

• MORITA Hiromi

  Chemical Technology Research Laboratories, Daiichi Pharmaceutical Co., Ltd.

• KIKUCHI Hiroshi

  Drug Metabolism & Physicochemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd.

• ARAMAKI Yukihiko

  Faculty of Pharmaceutical Sciences, Tokyo University of Pharmacy and Life Science

• AMIDON Gordon L.

  College of Pharmacy, University of Michigan

抄録

  DX-9065a, a newly synthesized anticoagulant that selectively inhibits factor Xa, is a zwitterion and has characteristics of high water solubility and low lipophilicity. We predicted the fraction absorbed (Fa) of DX-9065a to be approximately 15-35% in humans, based on the boundary layer theory using the intestinal perfusion method in rats. However, human oral bioavailability was 2-3% in clinical trials, and the result of actual human bioavailability was lower than that of the predicted Fa. Thus, in this report, the reason for low oral bioavailability of DX-9065a was examined by in vitro and in vivo experiments. The factors affecting oral bioavailability of DX-9065a were not the hepatic first-pass effect, degradation of the drug in intestinal fluid, nor the interaction of the drug with the intestinal mucin. Furthermore, no effect of P-gp efflux was observed. Oral absorption of the drug in rats with bile duct ligation was significantly higher than that in normal rats with bioavailability of 17 and 3%, respectively. It was confirmed that bile acids inhibited DX-9065a absorption because DX-9065a interacted with bile acids to form insoluble complexes. The results suggest that the complex formation of DX-9065a with bile acids in the intestinal tract is an important factor affecting absorption of DX-9065a.<br>

収録刊行物

• Ｄｒｕｇ　Ｍｅｔａｂｏｌｉｓｍ　ａｎｄ　Ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ

  Ｄｒｕｇ　Ｍｅｔａｂｏｌｉｓｍ　ａｎｄ　Ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ 22 (1), 26-32, 2007

  日本薬物動態学会

キーワード

• DX-9065a
• anticoagulant
• factor Xa inhibitor
• membrane permeability
• rat
• bioavailability
• bile acid

詳細情報

• CRID: 1390001205179147008
• NII論文ID: 10018732905
• NII書誌ID: AA1162652X
• DOI: 10.2133/dmpk.22.26
• ISSN: 18800920
• ISSN: 13474367
• Web Site: http://api.elsevier.com/content/article/PII:S1347436715302299?httpAccept=text/xml
• Web Site: http://api.elsevier.com/content/article/PII:S1347436715302299?httpAccept=text/plain
• Web Site: https://search.jamas.or.jp/link/ui/2007232882
• 本文言語コード: en
• データソース種別:
  • JaLC
  • Crossref
  • CiNii Articles
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