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Research ArticleArticle

Pharmacodynamics of Immunosuppression by Mycophenolic Acid: Inhibition of Both Lymphocyte Proliferation and Activation Correlates with Pharmacokinetics

Jan F. Gummert, Markus J. Barten, Steve W. Sherwood, Teun van Gelder and Randall E. Morris
Journal of Pharmacology and Experimental Therapeutics December 1999, 291 (3) 1100-1112;
Jan F. Gummert
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Markus J. Barten
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Steve W. Sherwood
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Teun van Gelder
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Randall E. Morris
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Abstract

Mechanisms of immunosuppressive action of mycophenolic acid (MPA) on rat lymphocytes and correlations among MPA plasma concentrations (pharmacokinetics) and its suppression of immune functions (pharmacodynamics) were studied in vitro and in vivo. In vitro, MPA inhibited concanavalin A-stimulated lymphocyte proliferation in blood [tritium-labeled thymidine ([3H]TdR) incorporation, percentage of lymphocytes positive for proliferating cell nuclear antigen, and in S-G2M by flow cytometry] and activation (percentage of lymphocytes expressing CD25 or CD134). Maximum percent inhibitions (Imax) of lymphocyte functions and concentrations of MPA (mg/l in blood) inhibiting 50% of Imax (IC50) were 99%/0.14 mg/l for [3H]TdR, 93%/0.28 mg/l for S-G2M, 74%/0.29 mg/l for CD25, and 83%/0.24 mg/l for CD134. Blood sampled at different times after single or multiple oral MPA administrations at four dose levels was assayed for lymphocyte functions and MPA plasma concentrations. Imax (%) and IC50 (mg/l in plasma by HPLC) were 98 to 99%/0.18 to 0.19 mg/l for [3H]TdR, 88 to 98%/0.70 to 0.83 mg/l for S-G2M, 60 to 63%/0.65 to 0.81 mg/l for CD25, and 72 to 77%/0.61 to 0.74 mg/l for CD134. IC50 values for S-G2M, CD25, and CD134 were higher after multiple daily treatments than after a single dose. There were clear and direct relationships among MPA dose levels, kinetics of MPA plasma concentrations, and dynamics of lymphocyte functions. MPA treatment in vitro and in vivo inhibits not only mitogen-stimulated lymphocyte proliferation in whole blood but also lymphocyte expression of cell surface cytokine receptors. These two different mechanisms of action may contribute to the therapeutic efficacy of MPA in vivo.

Footnotes

  • Send reprint requests to: Randall E. Morris, M.D., Transplantation Immunology, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA 94305-5407. E-mail: rem{at}leland.stanford.edu

  • ↵1 This work was supported by Deutsche Forschungsgemeinschaft Grant Gu 472/1-1 (J.F.G.) and by the Hedco Foundation and the Ralph and Marian Falk Trust.

  • Abbreviations:
    MPA
    mycophenolic acid
    IMPDH
    inosine 5′-monophosphate dehydrogenase
    [3H]TdR
    tritium-labeled thymidine
    AUC
    area under the plasma concentration-time curve
    AUC0-∞
    area under the plasma concentration-time curve
    AUE0–24 h
    area under the pharmacodynamic effect-time curve during the 24 h after dosing
    WBC
    white blood cell
    CM
    culture medium
    MMF
    mycophenolate mofetil
    IL
    interleukin
    MPAG
    mycophenolic acid glucuronide
    SNK
    Student-Newman-Keuls
    FITC
    fluorescein isothiocyanate
    PCNA
    proliferating cell nuclear antigen
    PI
    propidium iodide
    • Received October 23, 1998.
    • Accepted June 30, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 3
1 Dec 1999
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Research ArticleArticle

Pharmacodynamics of Immunosuppression by Mycophenolic Acid: Inhibition of Both Lymphocyte Proliferation and Activation Correlates with Pharmacokinetics

Jan F. Gummert, Markus J. Barten, Steve W. Sherwood, Teun van Gelder and Randall E. Morris
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1100-1112;

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Research ArticleArticle

Pharmacodynamics of Immunosuppression by Mycophenolic Acid: Inhibition of Both Lymphocyte Proliferation and Activation Correlates with Pharmacokinetics

Jan F. Gummert, Markus J. Barten, Steve W. Sherwood, Teun van Gelder and Randall E. Morris
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1100-1112;
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