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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|Li, Xiaobing; Jusko, William J; Cao, Yanguang (2018) Role of Interstitial Fluid Turnover on Target Suppression by Therapeutic Biologics Using a Minimal Physiologically Based Pharmacokinetic Model. J Pharmacol Exp Ther 367:1-8|
|Ayyar, Vivaswath S; Sukumaran, Siddharth; DuBois, Debra C et al. (2018) Modeling Corticosteroid Pharmacogenomics and Proteomics in Rat Liver. J Pharmacol Exp Ther 367:168-183|
|Zhu, Xu; Shen, Xiaomeng; Qu, Jun et al. (2018) Proteomic Analysis of Combined Gemcitabine and Birinapant in Pancreatic Cancer Cells. Front Pharmacol 9:84|
|Pierre, Kamau; Rao, Rohit T; Hartmanshenn, Clara et al. (2018) Modeling the Influence of Seasonal Differences in the HPA Axis on Synchronization of the Circadian Clock and Cell Cycle. Endocrinology 159:1808-1826|
|Rao, Rohit T; Scherholz, Megerle L; Androulakis, Ioannis P (2018) Modeling the influence of chronopharmacological administration of synthetic glucocorticoids on the hypothalamic-pituitary-adrenal axis. Chronobiol Int 35:1619-1636|
|Jusko, William J (2017) Clarification of contraceptive drug pharmacokinetics in obesity. Contraception 95:10-16|
|Koch, Gilbert; Jusko, William J; Schropp, Johannes (2017) Target mediated drug disposition with drug-drug interaction, Part II: competitive and uncompetitive cases. J Pharmacokinet Pharmacodyn 44:27-42|
|Rao, Rohit T; Androulakis, Ioannis P (2017) Modeling the Sex Differences and Interindividual Variability in the Activity of the Hypothalamic-Pituitary-Adrenal Axis. Endocrinology 158:4017-4037|
|Rao, Rohit T; Scherholz, Megerle L; Hartmanshenn, Clara et al. (2017) On the analysis of complex biological supply chains: From Process Systems Engineering to Quantitative Systems Pharmacology. Comput Chem Eng 107:100-110|
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