Second generation model for prednisolone pharmacodynamics in the rat

  • Alice I. Nichols
  • F. Douglas Boudinot
  • William J. Jusko
Article
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Abstract

An improved model describing receptor/gene-mediated pharmacodynamics of prednisolone is presented which consists of seven differential equations. Data for plasma prednisolone concentrations, free hepatic glucocorticoid receptors, and hepatic tyrosine aminotransferase activity (TAT) following low (5 mg/kg) and high (50 mg/kg) doses of prednisolone are used to quantitate the kinetics and dynamics of this synthetic steroid in the rat. In contrast to the earlier model, the newer model provides for a coupling and simultaneous fitting of receptor and TAT data and is able to describe the recycling of receptors between cytosol and nucleus and the return of cytosolic receptors to baseline following glucocorticoid elimination. A numerical technique to determine the efficiency of TAT induction based on area under the curve calculations is presented, which supports the hypothesis that nonlinear dose-response effects are due to dose and time-dependent receptor depletion in the cytosol. Simulations are presented to examine the major determinants of corticosteroid effects and to compare the effects of single-and multiple-dose regimens in maximizing drug effects.

Key words

prednisolone pharmacodynamics glucocorticoid receptors modeling 
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Copyright information

© Plenum Publishing Corporation 1989

Authors and Affiliations

  • Alice I. Nichols
    • 1
  • F. Douglas Boudinot
    • 2
  • William J. Jusko
    • 1
  1. 1.Department of Pharmaceutics, School of PharmacyState University of New York at BuffaloBuffalo
  2. 2.Department of Pharmaceutics, College of PharmacyUniversity of GeorgiaAthens

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