In Vitro Inhibition of CYP2C9-Mediated Warfarin 7-Hydroxylation by Iguratimod : Possible Mechanism of Iguratimod-Warfarin Interaction

• Yamaori Satoshi

  Department of Pharmacy, Shinshu University Hospital Department of Biochemical Pharmacology and Toxicology, Graduate School of Medicine, Shinshu University

• Takami Ken

  School of Medicine, Shinshu University

• Shiozawa Ayaka

  Department of Pharmacy, Shinshu University Hospital Department of Biochemical Pharmacology and Toxicology, Graduate School of Medicine, Shinshu University

• Sakuyama Kanako

  Department of Pharmacy, Shinshu University Hospital

• Matsuzawa Naoki

  Department of Pharmacy, Shinshu University Hospital

• Ohmori Shigeru

  Department of Pharmacy, Shinshu University Hospital Department of Biochemical Pharmacology and Toxicology, Graduate School of Medicine, Shinshu University

書誌事項

タイトル別名

• <i>In Vitro</i> Inhibition of CYP2C9-Mediated Warfarin 7-Hydroxylation by Iguratimod
• Possible Mechanism of Iguratimod–Warfarin Interaction

抄録

Iguratimod is a novel disease-modifying antirheumatic drug. A blue letter (safety advisory) for drug interaction between iguratimod and warfarin was issued by the Ministry of Health, Labour and Welfare of Japan in May 2013. Iguratimod may affect warfarin metabolism catalyzed by CYP. However, it is not clear whether iguratimod inhibits warfarin oxidation. This study was performed to investigate the effects of iguratimod on warfarin 7-hydroxylation with human liver microsomes (HLMs) and recombinant CYP enzymes. Iguratimod concentration-dependently inhibited R,S-warfarin 7-hydroxylase activity of HLMs with an IC₅₀ value of 15.2 µM. The inhibitory effect was examined with S-warfarin and R-warfarin to determine which enantiomer was more potently inhibited by iguratimod. Iguratimod potently inhibited the S-warfarin 7-hydroxylase activity of HLMs with an IC₅₀ value of 14.1 µM, but showed only slight inhibition of R-warfarin 7-hydroxylation. Furthermore, iguratimod inhibited the S-warfarin 7-hydroxylase activity of recombinant CYP2C9.1 (rCYP2C9.1) and rCYP2C9.3 in a concentration-dependent manner with IC₅₀ values of 10.8 and 20.1 µM, respectively. Kinetic analysis of the inhibition of S-warfarin 7-hydroxylation by iguratimod indicated competitive-type inhibition for HLMs and rCYP2C9.1 but mixed-type inhibition for rCYP2C9.3. The K_i values for HLMs, rCYP2C9.1, and rCYP2C9.3 were 6.74, 4.23, and 14.2 µM, respectively. Iguratimod did not exert metabolism-dependent inhibition of S-warfarin 7-hydroxylation. These results indicated that iguratimod is a potent direct inhibitor of CYP2C9-mediated warfarin 7-hydroxylation and that its inhibitory effect on CYP2C9.1 was more sensitive than that on CYP2C9.3.

収録刊行物

• Ｂｉｏｌｏｇｉｃａｌ　＆　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｂｕｌｌｅｔｉｎ

  Ｂｉｏｌｏｇｉｃａｌ　＆　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｂｕｌｌｅｔｉｎ 38 (3), 441-447, 2015

  公益社団法人 日本薬学会

キーワード

• iguratimod
• warfarin
• CYP2C9
• inhibition
• drug–drug interaction
• polymorphism

詳細情報

• CRID: 1390001204634508544
• NII論文ID: 130004872267
• NII書誌ID: AA10885497
• DOI: 10.1248/bpb.b14-00711
• ISSN: 13475215
• ISSN: 09186158
• NDL書誌ID: 026193295
• PubMed: 25757926
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I026193295
• Web Site: https://www.jstage.jst.go.jp/article/bpb/38/3/38_b14-00711/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2015360256
• 本文言語コード: en
• データソース種別:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
  • KAKEN
• 抄録ライセンスフラグ: 使用不可