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 their 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. 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, age, and disease perturbations of steroid disposition and effects.
One specific aim i s to test and extend our current models of prednisolone disposition and dynamics in the rat (entailing seven differential equations and accounting for steroid kinetics, hepatic receptor binding, and hepatic enzyme activity) by examining the effects of single versus prolonged administration of the steroid. A second specific aim is to set up a similar experimental system in the rat for dexamethasone and methylprednisolone to assess the effects of prodrugs, the role of reversible metabolism, and to expand the kinetic/receptor/dynamic profile of the steroid.
Our third aim i s to use our receptor binding system to gain unique insights into the role of plasma protein binding in affecting corticosteroid disposition and effects. The fourth specific aim is to examine the effects of major organ dysfunction (inflammatory and renal disease) on methylprednisolone kinetics and dynamics in the rat. Finally, human studies of steroid disposition and pharmacologic effects will accompany these studies. Our fifth aim is to scale-up and extend our kinetic/dynamic models to fully characterize the dose and time patterns of several corticosteroid effects in man. In total, these studies will assist in the design and implementation of more efficacious and less toxic corticosteroid treatment regimens in patients.
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