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Research ArticleArticle

Glutaredoxin and Thioredoxin Can Be Involved in Producing the Pharmacologically Active Metabolite of a Thienopyridine Antiplatelet Agent, Prasugrel

Katsunobu Hagihara, Miho Kazui, Atsushi Kurihara, Kazuishi Kubota and Toshihiko Ikeda
Drug Metabolism and Disposition February 2011, 39 (2) 208-214; DOI: https://doi.org/10.1124/dmd.110.035196
Katsunobu Hagihara
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Miho Kazui
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Atsushi Kurihara
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Kazuishi Kubota
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Toshihiko Ikeda
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Abstract

A thienopyridine antiplatelet agent, prasugrel, is rapidly hydrolyzed to a thiolactone metabolite (R-95913, 2-[2-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl)ethanone). R-95913 is oxidized by hepatic cytochromes P450 to the pharmacologically active metabolite R-138727 (2-[1–2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-mercapto-3-piperidinylidene]acetic acid). One possible intermediate in the in vitro bioactivation pathway is a glutathione conjugate, R-133490, which could be reduced to generate R-138727 in the presence of a reducing agent such as glutathione. In this study, enzymes in human liver cytosols were found to accelerate reduction of R-133490 leading to the formation of R-138727. To explore the possible reductive enzymes, we separated the various proteins in human liver cytosol based on size using gel filtration chromatography. Two active peaks were detected and found to contain thioredoxin and glutaredoxin, respectively. In addition, recombinant human glutaredoxin and thioredoxin promoted the formation of R-138727 from R-133490 with much higher activity for glutaredoxin than for thioredoxin. This study is the first in vitro observation indicating that glutaredoxin and thioredoxin in human liver are active in reducing the mixed disulfide formed between xenobiotics and glutathione.

Footnotes

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

    doi:10.1124/dmd.110.035196.

  • ABBREVIATIONS:

    R-95913
    2-[2-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl)ethanone
    R-138727
    2-[1–2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-mercapto-3-piperidinylidene]acetic acid
    LC-MS/MS
    liquid chromatography equipped with tandem mass spectrometry
    HPLC
    high-performance liquid chromatography
    FPLC
    fast protein liquid chromatography
    PAGE
    polyacrylamide gel electrophoresis
    TBS
    Tris-buffered saline
    HRP
    horseradish peroxidase
    FA
    formic acid
    KPB
    potassium phosphate buffer
    CLint
    intrinsic clearance
    prasugrel
    2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine.

  • Received June 29, 2010.
  • Accepted October 25, 2010.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (2)
Drug Metabolism and Disposition
Vol. 39, Issue 2
1 Feb 2011
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Research ArticleArticle

Glutaredoxin and Thioredoxin Can Be Involved in Producing the Pharmacologically Active Metabolite of a Thienopyridine Antiplatelet Agent, Prasugrel

Katsunobu Hagihara, Miho Kazui, Atsushi Kurihara, Kazuishi Kubota and Toshihiko Ikeda
Drug Metabolism and Disposition February 1, 2011, 39 (2) 208-214; DOI: https://doi.org/10.1124/dmd.110.035196

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Research ArticleArticle

Glutaredoxin and Thioredoxin Can Be Involved in Producing the Pharmacologically Active Metabolite of a Thienopyridine Antiplatelet Agent, Prasugrel

Katsunobu Hagihara, Miho Kazui, Atsushi Kurihara, Kazuishi Kubota and Toshihiko Ikeda
Drug Metabolism and Disposition February 1, 2011, 39 (2) 208-214; DOI: https://doi.org/10.1124/dmd.110.035196
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