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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Pharmacology A Study Section (PHRA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
State University of New York at Buffalo
Other Health Professions
Schools of Pharmacy
United States
Zip Code
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
Jusko, William J (2017) Perspectives on variability in pharmacokinetics of an oral contraceptive product. Contraception 95:5-9
Ayyar, Vivaswath S; DuBois, Debra C; Almon, Richard R et al. (2017) Mechanistic Multi-Tissue Modeling of Glucocorticoid-Induced Leucine Zipper Regulation: Integrating Circadian Gene Expression with Receptor-Mediated Corticosteroid Pharmacodynamics. J Pharmacol Exp Ther 363:45-57
Ayyar, Vivaswath S; Almon, Richard R; DuBois, Debra C et al. (2017) Functional proteomic analysis of corticosteroid pharmacodynamics in rat liver: Relationship to hepatic stress, signaling, energy regulation, and drug metabolism. J Proteomics 160:84-105
Kamisoglu, Kubra; Acevedo, Alison; Almon, Richard R et al. (2017) Understanding Physiology in the Continuum: Integration of Information from Multiple -Omics Levels. Front Pharmacol 8:91
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
Koch, Gilbert; Jusko, William J; Schropp, Johannes (2017) Target-mediated drug disposition with drug-drug interaction, Part I: single drug case in alternative formulations. J Pharmacokinet Pharmacodyn 44:17-26
Bae, Seul-A; Androulakis, Ioannis P (2017) The Synergistic Role of Light-Feeding Phase Relations on Entraining Robust Circadian Rhythms in the Periphery. Gene Regul Syst Bio 11:1177625017702393
Li, Xiaonan; DuBois, Debra C; Almon, Richard R et al. (2017) Modeling Sex Differences in Pharmacokinetics, Pharmacodynamics, and Disease Progression Effects of Naproxen in Rats with Collagen-Induced Arthritis. Drug Metab Dispos 45:484-491

Showing the most recent 10 out of 172 publications