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Roles of CYP2C9 and its variants (CYP2C9*2 and CYP2C9*3) in the metabolism of 6-methoxy-2-napthylacetic acid, an active metabolite of the prodrug nabumetone

  • Kaori Matsumoto
  • Tetsuya Hasegawa
  • Kosuke Ohara
  • Chihiro Takei
  • Masayuki AkimotoEmail author
Original Article
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Abstract

Nabumetone is a prodrug, used as an anti-inflammation agent and having the active metabolite 6-methoxy-2-naphthylacetic acid (6-MNA). The role of the polymorphic enzyme responsible for the 6-O-demethylation of 6-MNA to 6-hydroxy-2-naphtylacetic acid (6-HNA) was studied using recombinant cytochrome CYP2C9 microsomes (CYP2C9.1, CYP2C9.2 and CYP2C9.3) and human liver microsomes of known genotypes of CYP2C9. Utilizing recombinant CYP2C9.1, Vmax and Vmax/Km values of 6.3 ± 3.3 pmol/min/pmol P450 and 12.4 ± 4.7 nL/min/pmol P450, respectively, were obtained for the 6-MNA metabolism, and were almost similar to those in CYP2C9.2. In contrast, the Vmax/Km value in recombinant CYP2C9.3 was about one-third that of CYP2C9.1. In kinetic studies using liver microsomes of humans genotyped for the CYP2C9 genes, a sample genotyped as *3/*3 revealed about 4- to sixfold lower intrinsic clearance for 6-HNA formation than did samples genotyped as *1/*1. No appreciable differences were observed in kinetic parameters for 6-HNA formation in *1/*2 and *1/*3, while *2/*2 microsomes was comparable to wild type microsomes. In addition, S-warfarin 7-hydroxylation by recombinant CYP2C9.1 and CYP2C9.3 was inhibited by 6-MNA in a mixed manner. The apparent Ki value of 6-MNA on S-warfarin 7-hydroxylation by CYP2C9.3 was higher than that by CYP2C9.1. These results may provide valuable information for optimizing the anticoagulant activity of warfarin when nabumetone is co-administrated to patients.

Keywords

Nabumetone 6-MNA CYP2C9 Liver microsomes Polymorphism Warfarin 

Notes

Compliance with ethical standards

Conflict of interest

None of the authors has any conflicts of interest or any financial ties to disclose.

Ethical standards

This work complies with all ethical standards.

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Copyright information

© The Korean Society of Pharmaceutical Sciences and Technology 2019

Authors and Affiliations

  • Kaori Matsumoto
    • 1
  • Tetsuya Hasegawa
    • 1
  • Kosuke Ohara
    • 1
  • Chihiro Takei
    • 1
  • Masayuki Akimoto
    • 1
    Email author
  1. 1.Faculty of Pharmaceutical SciencesJosai International UniversityToganeJapan

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