Characterization of the major factors determining corticosteroid pharmacodynamics and receptor binding and the development of improved mathematical models for quantitating the pharmacodynamics of the steroids of major clinical importance will be sought. These drugs exert many of their hormonal, anti-inflammatory, and immunosuppressive effects by diffusion into cells, reversible binding to cytosolic receptors, and DNA/mRNA/secondary messenger-mediated synthesis of effector proteins or enzymes in sensitive cells. Some effects (cell trafficking) are rapid in onset and are probably non-genomic. Kinetic/Dynamic models and animal experimental systems to quantitate these processes will be tested, improved, and applied to humans. The major hypothesis is that realistic and comprehensive kinetic/dynamic models of corticosteroid action are feasible which permit more mechanistic insights into dosage, drug, and pathophysiologic perturbations of steroid disposition and effects.
one specific aim i s to extend our current gene-mediated models of steroid disposition and dynamics in the rat (entailing multiple differential equations and accounting for receptor binding and hepatic enzyme activity) by inclusion of mRNA measurements.
A second aim i s to evaluate the role of transcortin binding in affecting steroid action with the expectation that this steroid binding protein may partly control tissue selectivity in responses.
The third aim i s to expand models for steroid effects on cell trafficking by measurements of diverse cells and utilization of a rat model for greater mechanistic insights.
The fourth aim i s to continue and extend the application of pharmacodynamic models in human studies by determining the effects of gender and estrogens (OC) on steroid kinetics and dynamics. These studies will assist in the design and implementation of more efficacious and less toxic corticosteroid dosage regimens in patients and will continue the generation of an important general class of pharmacodynamic models which apply to drugs causing pharmacologic effects by indirect mechanisms.
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