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Research ArticleMetabolism, Transport, and Pharmacogenomics

Modeling Corticosteroid Pharmacokinetics and Pharmacodynamics, Part I: Determination and Prediction of Dexamethasone and Methylprednisolone Tissue Binding in the Rat

Vivaswath S. Ayyar, Dawei Song, Debra C. DuBois, Richard R. Almon and William J. Jusko
Journal of Pharmacology and Experimental Therapeutics August 2019, 370 (2) 318-326; DOI: https://doi.org/10.1124/jpet.119.257519
Vivaswath S. Ayyar
Departments of Pharmaceutical Sciences (V.S.A., D.S., D.C.D., R.R.A., W.J.J.) and Biological Sciences (D.C.D., R.R.A.), State University of New York at Buffalo, Buffalo, New York
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Dawei Song
Departments of Pharmaceutical Sciences (V.S.A., D.S., D.C.D., R.R.A., W.J.J.) and Biological Sciences (D.C.D., R.R.A.), State University of New York at Buffalo, Buffalo, New York
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Debra C. DuBois
Departments of Pharmaceutical Sciences (V.S.A., D.S., D.C.D., R.R.A., W.J.J.) and Biological Sciences (D.C.D., R.R.A.), State University of New York at Buffalo, Buffalo, New York
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Richard R. Almon
Departments of Pharmaceutical Sciences (V.S.A., D.S., D.C.D., R.R.A., W.J.J.) and Biological Sciences (D.C.D., R.R.A.), State University of New York at Buffalo, Buffalo, New York
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William J. Jusko
Departments of Pharmaceutical Sciences (V.S.A., D.S., D.C.D., R.R.A., W.J.J.) and Biological Sciences (D.C.D., R.R.A.), State University of New York at Buffalo, Buffalo, New York
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  • Fig. 1.
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    Fig. 1.

    Percent binding vs. total plasma steroid concentration for MPL (left) and DEX (right) in male (black squares), pooled female (green diamonds), estrus-phased female (orange diamonds), and proestrus-phased female (blue triangles) rat plasma. The inset depicts bound vs. free steroid concentrations of MPL in male and pooled female rat plasma.

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    Fig. 2.

    MPL (top) and DEX (bottom) tissue-to-plasma partition coefficients (KP) obtained in vivo by bolus injection in male rats (black bars), infusion in male rats (gray bars), or bolus injection in female rats (dashed gray bars). Error bars represent 1 S.D. from the mean.

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    Fig. 3.

    Time course of in vitro stability of MPL in liver homogenates prepared at 3× (red), 4× (blue), 6× (orange), and 10× (green) dilutions from freshly harvested male (left) and female (right) livers. Symbols represent the mean ± S.D. (n = 3 per time point), the solid line depicts the first-order loss kinetics of MPL in male liver homogenates, and the dashed lines connect the data points.

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    Fig. 4.

    Binding of MPL in homogenates prepared from male rat liver (left), female rat liver (middle), and male rat lung (right) at initial concentrations of 10 μg/ml. Symbols depict the mean ± S.D. of the binding factor (Cbound/Cfree) across four dilutions of tissue homogenate. The dashed line represents the best-fit line extrapolated to an undiluted state of tissue (dil = 1).

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    Fig. 5.

    Binding of DEX in homogenates prepared from male rat liver (left), female rat liver (middle), and male rat lung (right) at initial concentrations of 1 μg/ml (gray) and/or 10 μg/ml (black). Symbols depict the mean ± S.D. of the binding factor (Cbound/Cfree) across four dilutions of tissue homogenate. The dashed line represents the best-fit line extrapolated to an undiluted state of tissue (dil = 1).

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    TABLE 1

    Comparison of tissue KP values for MPL determined by different methods Values are listed as the mean ± S.D.

    Tissue (Sex)In Vivo KPfu,t (in vitro)In Vitro KPMethod 1Method 2Method 3
    Liver (male)13.4 ± 0.9a0.162 ± 0.012.5 ± 0.21.20.90.8
    13.3 ± 1.4b
    Liver (female)11.4 ± 1.4a0.066 ± 0.0036.1 ± 0.4
    Lung (male)2.3 ± 0.0b0.192 ± 0.012.1 ± 0.11.31.00.9
    Muscle (male)1.8 ± 0.4b0.298 ± 0.051.4 ± 0.20.90.80.6
    • ↵a Intramuscular injection.

    • ↵b Subcutaneous infusion.

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    TABLE 2

    Comparison of tissue KP values for DEX determined by different methods Values are listed as the mean ± S.D.

    Tissue (Sex)In Vivo KPfu,t(invitro)In Vitro KPMethod 1Method 2Method 3
    Liver (male)5.5 ± 0.3a0.050 ± 0.0013.6 ± 0.5c1.30.70.6
    4.8 ± 0.5b0.068 ± 0.0012.6 ± 0.4d
    Liver (female)—0.059 ± 0.0043.0 ± 0.5c
    0.070 ± 0.0032.5 ± 0.4d
    Lung (male)0.53 ± 0.02a0.115 ± 0.0061.5 ± 0.3d1.40.80.6
    0.43 ± 0.05b
    Muscle (male)0.50 ± 0.0a0.236 ± 0.030.74 ± 0.1d0.90.60.34
    0.49 ± 0.04b
    • ↵a Subcutaneous injection.

    • ↵b Subcutaneous infusion.

    • ↵c Low DEX concentration (1 μg/ml).

    • ↵d High DEX concentration (10 μg/ml).

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    • Supplemental Data -

      Supplemental figures 1-3. 

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Journal of Pharmacology and Experimental Therapeutics: 370 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 370, Issue 2
1 Aug 2019
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Determination and Prediction of Steroid Tissue Binding

Vivaswath S. Ayyar, Dawei Song, Debra C. DuBois, Richard R. Almon and William J. Jusko
Journal of Pharmacology and Experimental Therapeutics August 1, 2019, 370 (2) 318-326; DOI: https://doi.org/10.1124/jpet.119.257519

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Determination and Prediction of Steroid Tissue Binding

Vivaswath S. Ayyar, Dawei Song, Debra C. DuBois, Richard R. Almon and William J. Jusko
Journal of Pharmacology and Experimental Therapeutics August 1, 2019, 370 (2) 318-326; DOI: https://doi.org/10.1124/jpet.119.257519
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