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Research ArticleArticle

Glucuronidation of Antiallergic Drug, Tranilast: Identification of Human UDP-Glucuronosyltransferase Isoforms and Effect of Its Phase I Metabolite

Miki Katoh, Tomohito Matsui and Tsuyoshi Yokoi
Drug Metabolism and Disposition April 2007, 35 (4) 583-589; DOI: https://doi.org/10.1124/dmd.106.013706
Miki Katoh
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Tomohito Matsui
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Tsuyoshi Yokoi
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Abstract

Tranilast is an oral antiallergic agent widely used in Japan. Recently, in Western populations, hyperbilirubinemia induced by tranilast was suspected during clinical trials. Tranilast has been reported to be mainly metabolized to a glucuronide and a phase I metabolite, 4-demethyltranilast (N-3). In the present study, we investigated the in vitro metabolism of tranilast in human liver and jejunum microsomes and recombinant UDP-glucuronosyltransferases (UGTs). The glucuronidation of tranilast was clarified to be mainly catalyzed by UGT1A1 in human liver and intestine. The Km values of tranilast glucuronosyltransferase activity were 51.5, 50.6, and 38.0 μM in human liver microsomes, human jejunum microsomes, and recombinant UGT1A1, respectively. The Vmax values were 10.4, 42.9, and 19.7 pmol/min/mg protein in human liver microsomes, human jejunum microsomes, and recombinant UGT1A1, respectively. When the intrinsic clearance was calculated using the in vitro kinetic parameters, microsomal protein content, and weight of tissues, tranilast glucuronosyltransferase activity was 2.5-fold higher in liver than in intestine. Tranilast glucuronosyltransferase activity was strongly inhibited by bilirubin, a typical UGT1A1 substrate, and N-3, indicating that the phase I metabolite could affect the tranilast glucuronosyltransferase activity. In the case of N-3 formation, the Km and Vmax values were 37.1 μM and 27.6 pmol/min/mg protein in human liver microsomes. The bilirubin glucuronosyltransferase activity was strongly inhibited by both tranilast and N-3, suggesting that tranilast-induced hyperbilirubinemia would be responsible for the inhibition by tranilast and N-3 of the bilirubin glucuronosyltransferase activity, as would the UGT1A1 genotype.

Footnotes

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

  • doi:10.1124/dmd.106.013706.

  • ABBREVIATIONS: N-3, 4-demethyltranilast; UGT, UDP-glucuronosyltransferase; N-4, 3-demethytranilast; UDP-GA, UDP-glucuronic acid; HPLC, high-performance liquid chromatography; IS, internal standard; CLint, intrinsic clearance.

    • Received November 5, 2006.
    • Accepted January 10, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 35 (4)
Drug Metabolism and Disposition
Vol. 35, Issue 4
1 Apr 2007
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Research ArticleArticle

Glucuronidation of Antiallergic Drug, Tranilast: Identification of Human UDP-Glucuronosyltransferase Isoforms and Effect of Its Phase I Metabolite

Miki Katoh, Tomohito Matsui and Tsuyoshi Yokoi
Drug Metabolism and Disposition April 1, 2007, 35 (4) 583-589; DOI: https://doi.org/10.1124/dmd.106.013706

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Research ArticleArticle

Glucuronidation of Antiallergic Drug, Tranilast: Identification of Human UDP-Glucuronosyltransferase Isoforms and Effect of Its Phase I Metabolite

Miki Katoh, Tomohito Matsui and Tsuyoshi Yokoi
Drug Metabolism and Disposition April 1, 2007, 35 (4) 583-589; DOI: https://doi.org/10.1124/dmd.106.013706
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