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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Pharmacodynamics and Pharmacogenomics of Methylprednisolone during 7-Day Infusions in Rats

Rohini Ramakrishnan, Debra C. DuBois, Richard R. Almon, Nancy A. Pyszczynski and William J. Jusko
Journal of Pharmacology and Experimental Therapeutics January 2002, 300 (1) 245-256; DOI: https://doi.org/10.1124/jpet.300.1.245
Rohini Ramakrishnan
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Debra C. DuBois
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Richard R. Almon
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Nancy A. Pyszczynski
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William J. Jusko
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Abstract

An array of adverse steroid effects was examined on a whole body, tissue, and molecular level. Groups of male adrenalectomized Wistar rats were subcutaneously implanted with Alzet mini-pumps giving zero-order release rates of 0, 0.1, and 0.3 mg/kg/h methylprednisolone for 7 days. The rats were sacrificed at various times during the 7-day infusion period. A two-compartment model with a zero order input could adequately describe the kinetics of methylprednisolone upon infusion. Blood lymphocyte counts dropped to a minimum by 6 h and were well characterized by the cell trafficking model. The time course of changes in body and organ (liver, spleen, thymus, gastrocnemius muscle, and lungs) weights was described using indirect response models. Markers of gene-mediated steroid effects included hepatic cytosolic free receptor density, receptor mRNA, tyrosine aminotransferase (TAT) mRNA, and TAT levels. Our fifth-generation model of acute corticosteroid pharmacodynamics was used to predict the time course of receptor/gene-mediated effects. An excellent agreement between the expected and observed receptor dynamics suggested that receptor events and mRNA autoregulation are not altered upon 7-day methylprednisolone dosing. However, the model indicated a decoupling between the receptor and TAT dynamics with this infusion. The strong tolerance seen in TAT mRNA induction could be partly accounted for by receptor down-regulation. An amplification of translation of TAT mRNA to TAT and/or a reduction in the enzyme degradation rate could account for the observed exaggerated TAT activity. Our results exemplify the importance of biological signal transduction variables in controlling receptor/gene-mediated steroid responses during chronic dosing.

Footnotes

  • This study was supported by Grant GM24211 from the National Institutes of Health.

  • Abbreviations

    TAT
    tyrosine aminotransferase
    GRE
    glucocorticoid response element
    MPL
    methylprednisolone
    CL
    clearance
    ABEC
    area between the baseline and effect curve
    GCR
    glucocorticoid receptor
    • Received June 14, 2001.
    • Accepted August 24, 2001.
    • The American Society for Pharmacology and Experimental Therapeutics
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    Journal of Pharmacology and Experimental Therapeutics: 300 (1)
    Journal of Pharmacology and Experimental Therapeutics
    Vol. 300, Issue 1
    1 Jan 2002
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    Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

    Pharmacodynamics and Pharmacogenomics of Methylprednisolone during 7-Day Infusions in Rats

    Rohini Ramakrishnan, Debra C. DuBois, Richard R. Almon, Nancy A. Pyszczynski and William J. Jusko
    Journal of Pharmacology and Experimental Therapeutics January 1, 2002, 300 (1) 245-256; DOI: https://doi.org/10.1124/jpet.300.1.245

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    Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

    Pharmacodynamics and Pharmacogenomics of Methylprednisolone during 7-Day Infusions in Rats

    Rohini Ramakrishnan, Debra C. DuBois, Richard R. Almon, Nancy A. Pyszczynski and William J. Jusko
    Journal of Pharmacology and Experimental Therapeutics January 1, 2002, 300 (1) 245-256; DOI: https://doi.org/10.1124/jpet.300.1.245
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