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Research ArticleArticle

Metabolism and Excretion of the Novel Bioreductive Prodrug PR-104 in Mice, Rats, Dogs, and Humans

Yongchuan Gu, Graham J. Atwell and William R. Wilson
Drug Metabolism and Disposition March 2010, 38 (3) 498-508; DOI: https://doi.org/10.1124/dmd.109.030973
Yongchuan Gu
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Graham J. Atwell
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William R. Wilson
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Abstract

PR-104 is the phosphate ester of a 3,5-dinitrobenzamide nitrogen mustard (PR-104A) that is reduced to active hydroxylamine and amine metabolites by reductases in tumors. In this study, we evaluate the excretion of [3H]PR-104 in mice and determine its metabolite profile in mice, rats, dogs, and humans after a single intravenous dose. Total radioactivity was rapidly and quantitatively excreted in mice, with cumulative excretion of 46% in urine and 50% in feces. The major urinary metabolites in mice were products from oxidative N-dealkylation and/or glutathione conjugation of the nitrogen mustard moiety, including subsequent mercapturic acid pathway metabolites. A similar metabolite profile was seen in mouse bile, mouse plasma, and rat urine and plasma. Dogs and humans also showed extensive thiol conjugation but little evidence of N-dealkylation. Humans, like rodents, showed appreciable reduced metabolites in plasma, but concentrations of the cytotoxic amine metabolite (PR-104M) were higher in mice than humans. The most conspicuous difference in metabolite profile was the much more extensive O-β-glucuronidation of PR-104A in dogs and humans than in rodents. The structure of the O-β-glucuronide (PR-104G) was confirmed by independent synthesis. Its urinary excretion was responsible for 13 ± 2% of total dose in humans but only 0.8 ± 0.1% in mice. Based on these metabolite profiles, biotransformation of PR-104 in rodents is markedly different from that in humans, suggesting that rodents may not be appropriate for modeling human biotransformation and toxicology of PR-104.

Footnotes

  • This work was supported in part by the Health Research Council of New Zealand [Grant 08/103]; and a Technology in Industry Fellowship from the Foundation for Research, Science, and Technology, New Zealand (to Y.G.).

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

    doi:10.1124/dmd.109.030973.

  • Y.G. and G.J.A. have no conflicts of interest to disclose. William R. Wilson is a founding scientist, stockholder, and consultant to Proacta, Inc.

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

  • ABBREVIATIONS:

    PR-104A
    2-((2-bromoethyl)-2-{[(2-hydroxyethyl)-amino]-carbonyl}-4,6-dinitroanilino)-ethyl methanesulfonate
    HPLC
    high-performance liquid chromatography
    MS
    mass spectrometry
    i-Pr2O
    isopropyl ether
    HRMS
    high-resolution mass spectrometry
    MS/MS
    tandem mass spectrometry
    S9
    9000g postmitochondrial supernatant
    amu
    atomic mass unit
    AUC
    area under the concentration-time curve
    SN-38
    7-ethyl-10-hydroxycamptothecin
    1
    2,3,4-tri-O-acetyl-1-bromo-1-deoxy-α-d-glucuronate
    2
    (2R,3S,4S,5S,6S)-2-[2-[2-[(2-bromoethyl)[2-(methylsulfonyloxy)ethyl]amino]-3,5-dinitrobenzamido]ethoxy]-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate
    3
    2-chloro-N-(2-hydroxyethyl)-3,5-dinitrobenzamide
    4
    2-(aziridin-1-yl)-N-(2-hydroxyethyl)3,5-dinitrobenzamide.

    • Received October 29, 2009.
    • Accepted December 17, 2009.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (3)
Drug Metabolism and Disposition
Vol. 38, Issue 3
1 Mar 2010
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Research ArticleArticle

Metabolism and Excretion of the Novel Bioreductive Prodrug PR-104 in Mice, Rats, Dogs, and Humans

Yongchuan Gu, Graham J. Atwell and William R. Wilson
Drug Metabolism and Disposition March 1, 2010, 38 (3) 498-508; DOI: https://doi.org/10.1124/dmd.109.030973

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Research ArticleArticle

Metabolism and Excretion of the Novel Bioreductive Prodrug PR-104 in Mice, Rats, Dogs, and Humans

Yongchuan Gu, Graham J. Atwell and William R. Wilson
Drug Metabolism and Disposition March 1, 2010, 38 (3) 498-508; DOI: https://doi.org/10.1124/dmd.109.030973
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