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Research ArticleArticle

Metabolism of the c-Fos/Activator Protein-1 Inhibitor T-5224 by Multiple Human UDP-Glucuronosyltransferase Isoforms

Shinsuke Uchihashi, Hiroyuki Fukumoto, Makoto Onoda, Hiroyoshi Hayakawa, Shin-ichi Ikushiro and Toshiyuki Sakaki
Drug Metabolism and Disposition May 2011, 39 (5) 803-813; DOI: https://doi.org/10.1124/dmd.110.037952
Shinsuke Uchihashi
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Hiroyuki Fukumoto
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Makoto Onoda
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Hiroyoshi Hayakawa
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Shin-ichi Ikushiro
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Toshiyuki Sakaki
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Abstract

We developed 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl} propionic acid (T-5224) as a novel inhibitor of the c-Fos/activator protein-1 for rheumatoid arthritis therapy. We predicted the metabolism of T-5224 in humans by using human liver microsomes (HLM), human intestinal microsomes (HIM), recombinant human cytochrome P450 (P450), and UDP-glucuronosyltransferases (UGTs). T-5224 was converted to its acyl O-glucuronide (G2) by UGT1A1 and UGT1A3 and to its hydroxyl O-glucuronide (G3) by several UGTs, but it was not metabolized by the P450s. A comparison of the intrinsic clearances (CLint) between HLM and HIM suggested that the glucuronidation of T-5224 occurs predominantly in the liver. UGT1A1 showed a higher kcat/Km value than UGT1A3 for G2 formation, but a lower kcat/Km value than UGT1A3 for G3 formation. A high correlation was observed between G2 formation activity and UGT1A1-specific activity (β-estradiol 3-glucuronidation) in seven individual HLM. A high correlation was also observed between G2 formation activity and UGT1A1 content in the HLM. These results strongly suggest that UGT1A1 is responsible for G2 formation in human liver. In contrast, no such correlation was observed with G3 formation, suggesting that multiple UGT isoforms, including UGT1A1 and UGT1A3, are involved in G3 formation. G2 is also observed in rat and monkey liver microsomes as a major metabolite of T-5224, suggesting that G2 is not a human-specific metabolite. In this study, we obtained useful information on the metabolism of T-5224 for its clinical use.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.037952.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    T-5224
    3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl} propionic acid
    UGT
    UDP-glucuronosyltransferase
    P450
    cytochrome P450
    HLM
    human liver microsomes
    HIM
    human intestinal microsomes
    UDPGA
    UDP-glucuronic acid
    DMSO
    dimethyl sulfoxide
    HPLC
    high-performance liquid chromatography
    HCD
    high-energy collision dissociation
    CV
    coefficient of variation
    SN-38
    7-ethyl-10-hydroxycamptothecin
    PCR
    polymerase chain reaction.

  • Received December 27, 2010.
  • Accepted February 23, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (5)
Drug Metabolism and Disposition
Vol. 39, Issue 5
1 May 2011
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Research ArticleArticle

Metabolism of the c-Fos/Activator Protein-1 Inhibitor T-5224 by Multiple Human UDP-Glucuronosyltransferase Isoforms

Shinsuke Uchihashi, Hiroyuki Fukumoto, Makoto Onoda, Hiroyoshi Hayakawa, Shin-ichi Ikushiro and Toshiyuki Sakaki
Drug Metabolism and Disposition May 1, 2011, 39 (5) 803-813; DOI: https://doi.org/10.1124/dmd.110.037952

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Research ArticleArticle

Metabolism of the c-Fos/Activator Protein-1 Inhibitor T-5224 by Multiple Human UDP-Glucuronosyltransferase Isoforms

Shinsuke Uchihashi, Hiroyuki Fukumoto, Makoto Onoda, Hiroyoshi Hayakawa, Shin-ichi Ikushiro and Toshiyuki Sakaki
Drug Metabolism and Disposition May 1, 2011, 39 (5) 803-813; DOI: https://doi.org/10.1124/dmd.110.037952
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