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Research ArticleArticle

Glutathione and Mercapturic Acid Conjugates of Sulofenur and Their Activity against a Human Colon Cancer Cell Line

Xiangming Guan, Brianna N. Hoffman, Douglas C. McFarland, Kysa K. Gilkerson, Chandradhar Dwivedi, Angela K. Erickson, Scott Bebensee and Jill Pellegrini
Drug Metabolism and Disposition March 2002, 30 (3) 331-335; DOI: https://doi.org/10.1124/dmd.30.3.331
Xiangming Guan
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Brianna N. Hoffman
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Douglas C. McFarland
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Kysa K. Gilkerson
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Chandradhar Dwivedi
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Angela K. Erickson
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Scott Bebensee
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Jill Pellegrini
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Abstract

Sulofenur is one of the diarylsulfonylureas developed as an anticancer agent. Sulofenur possesses a broad spectrum of activity in several solid tumor models and has undergone extensive clinical trials based on its impressive preclinical activity. However, the clinical response of sulofenur has been disappointing because of the side effect of anemia. Furthermore, the anticancer mechanism of sulofenur and its diarylsulfonylurea analogs still remains unknown. Elucidation of the metabolic fates of sulofenur may help to delineate the mechanism and provide information to guide the structural modification for more potent anticancer agents with less side effects. We have identified a glutathione conjugate and a mercapturic acid conjugate from sulofenur-dosed rats with the aid of liquid chromatography/mass spectrometry. The fraction of the dose of sulofenur as the glutathione conjugate in the dosed-rat bile over 5 h was 0.12 ± 0.03%, and the mercapturic acid conjugate in urine over 24 h was 1.4 ± 0.7%. Protein binding of the glutathione conjugate and mercapturic acid conjugate was determined to be 20 ± 3 and 84 ± 2%, respectively, as opposed to >99% of sulofenur. The high protein binding of sulofenur requires a higher than in vitro dose, which is believed to cause the side effect of anemia. The significance of this metabolic pathway is that both conjugates were found to be glutathione reductase inhibitors and to possess anticancer activity comparable to sulofenur against human colon adenocarcinoma GC3/c1 cells, a sulofenur-sensitive cell line. These conjugates may serve as new leads for the development of novel anticancer agents.

Footnotes

  • This work was supported by a grant from the National Institutes of Health (CA79540), a Research Starter Grant from the College of Pharmacy of South Dakota State University, a South Dakota State University Research Support Grant (to X.G.), and a 1996–1997 Merck Research Scholar Award (to A.K.E.).

  • Abbreviations used are::
    GR
    glutathione reductase
    GSH
    glutathione
    LC/MS
    liquid chromatography/mass spectrometry
    BSA
    bovine serum albumin
    BCNU
    N, N-Bis(2-chloroethyl)-N-nitrosourea
    HPLC
    high-performance liquid chromatography
    • Received July 9, 2001.
    • Accepted November 19, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (3)
Drug Metabolism and Disposition
Vol. 30, Issue 3
1 Mar 2002
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Research ArticleArticle

Glutathione and Mercapturic Acid Conjugates of Sulofenur and Their Activity against a Human Colon Cancer Cell Line

Xiangming Guan, Brianna N. Hoffman, Douglas C. McFarland, Kysa K. Gilkerson, Chandradhar Dwivedi, Angela K. Erickson, Scott Bebensee and Jill Pellegrini
Drug Metabolism and Disposition March 1, 2002, 30 (3) 331-335; DOI: https://doi.org/10.1124/dmd.30.3.331

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Research ArticleArticle

Glutathione and Mercapturic Acid Conjugates of Sulofenur and Their Activity against a Human Colon Cancer Cell Line

Xiangming Guan, Brianna N. Hoffman, Douglas C. McFarland, Kysa K. Gilkerson, Chandradhar Dwivedi, Angela K. Erickson, Scott Bebensee and Jill Pellegrini
Drug Metabolism and Disposition March 1, 2002, 30 (3) 331-335; DOI: https://doi.org/10.1124/dmd.30.3.331
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