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Research ArticleArticle

Human Colorectal Carcinoma Cells In Vitro as a Means to Assess the Metabolism of Analogs of Mycophenolic Acid

Trevor J. Franklin, Vivien N. Jacobs, Geraint Jones and Patrick Plé
Drug Metabolism and Disposition March 1997, 25 (3) 367-370;
Trevor J. Franklin
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Vivien N. Jacobs
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Geraint Jones
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Patrick Plé
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Abstract

Cultures of the human colorectal carcinoma line, HT29, were used to assess the susceptibility to glucuronidation of the cytostatic, immunosuppressive drug mycophenolic acid (MPA) and 19 of its analogs. Removal of the metabolically vulnerable 7-hydroxyl group or its replacement by a fluorine atom, amino group, or nitrile group resulted in compounds that were completely resistant to metabolism, but that had substantially lower antiproliferative potency against the EMT6 carcinoma line that is unable to glucuronidate MPA. In compounds retaining the 7-hydroxy function replacement of the lactone moiety of the phthalane ring of MPA by either a cyclopentanone or a 6-membered lactam afforded some protection against metabolism, but also partially or completely suppressed antiproliferative activity. Some lipophilic substituents at position 2 of the hexenoic side chain in analogs with the 7-hydroxy function resulted in increased metabolism, whereas several substituents with increased steric bulk in this position (including benzyl, p-hydroxyphenyl, trifluoroacetamidophenyl,S-methyl, and methoxymethyl) markedly inhibited metabolism. The last three of these derivatives also maintained or exceeded the antiproliferative potency of MPA. We suggest that cultures of human colorectal carcinoma cells lines may provide a rapid and convenient means of assessing the susceptibility of novel synthetic compounds to both phase I and phase II metabolic conversions.

Footnotes

  • Send reprint requests to: Dr. Trevor J. Franklin, Zeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.

  • Abbreviations used are::
    MPA
    mycophenolic acid
    IMPDH
    inosine 5′-monophosphate dehydrogenase
    MTT
    3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide
    EMEM
    Eagle’s minimal essential medium
    DMSO
    dimethylsulfoxide
    OH
    hydroxy
    MM
    mycophenolate mofetil
    • Received September 12, 1996.
    • Accepted November 26, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 3
1 Mar 1997
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Research ArticleArticle

Human Colorectal Carcinoma Cells In Vitro as a Means to Assess the Metabolism of Analogs of Mycophenolic Acid

Trevor J. Franklin, Vivien N. Jacobs, Geraint Jones and Patrick Plé
Drug Metabolism and Disposition March 1, 1997, 25 (3) 367-370;

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Research ArticleArticle

Human Colorectal Carcinoma Cells In Vitro as a Means to Assess the Metabolism of Analogs of Mycophenolic Acid

Trevor J. Franklin, Vivien N. Jacobs, Geraint Jones and Patrick Plé
Drug Metabolism and Disposition March 1, 1997, 25 (3) 367-370;
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