Abstract

Major mechanisms determining receptor occupancy, expression of various genes, and alterations of several physiological systems will be studied and improved mathematical models for the in vivo pharmacokinetics, pharmacodynamics, and pharmacogenomics (PK/PD/PG) of corticosteroids will be sought. These important agents exert hormonal, immunosuppressive, and diverse biochemical effects by diffusion into cells, binding to cytosolic receptors, and increasing or decreasing turnover of mRNA and gene-mediated synthesis of diverse effector proteins or enzymes. Several systems will be examined with mechanistic, integrated, and comprehensive studies in shared animals given acute and chronic steroid doses.
Aim 1 will extend our current 5th-generation PK/PD/PG model for methylprednisolone (MP) effects on expression of select genes and on microarray-captured multiple genes in 3 tissues (liver, muscle, kidney) of adrenalectomized rats to consider the role of corticosterone (CST), circadian factors, and MP/CST interactions in normal rats.
Aim 2 focuses on diabetogenic effects of steroids including the critical enzyme PEPCK and systemic effects on glucose and insulin in normal and diabetic rats.
Aim 3 evaluates two inter-related adverse effects of steroids on muscle physiology (insulin resistance and atrophy) through expression of IRS-1, myostatin, and glutamine synthase.
Aim 4 assesses expression of select genes and lipid biomarkers accounting for steroid disruption of lipid biochemistry.
Aim 5 expands current efforts using high throughput gene arrays to develop bioinformatic and modeling tools to assess relationships underlying polygenic multi-tissue effects of steroids.
Aim 6 evolves several avenues of improved PK/PD/PG models that account for major mechanisms and processes controlling steroid actions with advancement of systems biological concepts. We will elucidate the pharmacologic basis of several interrelated systemic steroid effects and continue generation of important mechanistic PK/PD/PG concepts and models of drug action.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM024211-32
Application #
7455121
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Okita, Richard T
Project Start
1977-07-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
32
Fiscal Year
2008
Total Cost
$572,928
Indirect Cost

  Institution

Name
State University of New York at Buffalo
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260

  Publications

Ayyar, Vivaswath S; Sukumaran, Siddharth; DuBois, Debra C et al. (2018) Receptor/gene/protein-mediated signaling connects methylprednisolone exposure to metabolic and immune-related pharmacodynamic actions in liver. J Pharmacokinet Pharmacodyn 45:557-575
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
Zhu, Xu; Trueman, Sheryl; Straubinger, Robert M et al. (2018) Physiologically-based pharmacokinetic and pharmacodynamic models for gemcitabine and birinapant in pancreatic cancer xenografts. J Pharmacokinet Pharmacodyn 45:733-746
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
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
Li, Xiaonan; DuBois, Debra C; Almon, Richard R et al. (2017) Effect of Disease-Related Changes in Plasma Albumin on the Pharmacokinetics of Naproxen in Male and Female Arthritic Rats. Drug Metab Dispos 45:476-483

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