Major factors determining corticosteroid receptor binding and pharmacodynamics will be measured and improved mathematical models for quantitating the pharmacokinetics and pharmacodynamics (PK/PD) of corticosteroids will be sought. These important drugs exert their hormonal, immunosuppressive, and anti-inflammatory effects by diffusion into cells, reversible binding to cytosolic receptors, and then either have direct effects on biochemical processes or produce inhibition or stimulation of gene/mRNA-mediated synthesis of diverse effector proteins or enzymes. Realistic and comprehensive PK/PD models of corticosteroid action are feasible which permit more mechanistic insights into drug, dosage, and interaction factors which determine their effects.
One specific aim i s to extend our current gene-mediated models of steroid PK/PD in rats (measuring steroid disposition, hepatic receptors and mRNA, and hepatic TAT mRNA and TAT enzyme) to account for chronic dose effects, which are often highly deleterious.
The second aim i s to generalize our """"""""fourth-generation"""""""" receptor/gene PK/PD model for methylprednisolone to other steroids based on advanced QSAR principles and the expectation that alterations in pharmacokinetics and receptor binding will account for differences in responses.
The third aim will be to evolve improved methods for assessing drug interactions for indirect response processes with focus on joint effects of prednisolone and COX-2 inhibitors.
The fourth aim seeks to utilize quantitative gene array techniques to compare types and time patterns of suppression and enhanced expression of diverse genes altered by corticosteroids. These studies will improve the pharmacologic rationale of corticosteroid therapy as well as continue the generation of important pharmacodynamic models which apply to drugs causing effects by complex and indirect mechanisms.
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