Pharmacokinetics/pharmacodynamics of Glucocorticoids: Modeling the Glucocorticoid Receptor Dynamics and Dose/response of Commonly Prescribed Glucocorticoids

Overview

Journal ADMET DMPK

Specialty Pharmacology

Date 2024 Dec 23

PMID 39713253

Authors

David G Levitt

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: The main features of the dynamics of the glucocorticoid receptor (GR) have been known for 50 years: 1) in the absence of glucocorticoid (G), the receptor is localized entirely in the cytoplasm; 2) upon G binding, GR is converted into a tightly bound G form and is rapidly imported into the nucleus where it can bind DNA and modulate transcription; 3) nuclear export of GR is very slow; and 4) the nuclear form of GR can recycle through an unbound form, back to the bound transcription modulating form without leaving the nucleus.

Experimental Approach: A kinetic model that captures these features is presented, a set of model parameters for dexamethasone is derived, and the clinical implication for the commonly used glucocorticoids is discussed.

Key Results: At the high concentrations normally used to describe G pharmacodynamics, the model reduces to the standard Michaelis-Menten equation with a that is a function of 4 model parameters. At very low concentrations, it reduces to another Michaelis-Menten equation with about a 1000-fold greater affinity, at the nadir human endogenous cortisol concentration, the full model GR activity is 2.6 times greater than that predicted by extrapolation of the high concentration results.

Conclusion: The model is used to relate normal human 24-hour endogenous plasma cortisol levels to transcriptional activity and is applied to the commonly prescribed glucocorticoids (dexamethasone, methylprednisolone, prednisone) in an attempt to provide a pharmacological rationale for the very large therapeutic dosage range that has been traditionally used.

References

Caplan A, Fett N, Rosenbach M, Werth V, Micheletti R . Prevention and management of glucocorticoid-induced side effects: A comprehensive review: A review of glucocorticoid pharmacology and bone health. J Am Acad Dermatol. 2016; 76(1):1-9. DOI: 10.1016/j.jaad.2016.01.062. View

Meijsing S, Elbi C, Luecke H, Hager G, Yamamoto K . The ligand binding domain controls glucocorticoid receptor dynamics independent of ligand release. Mol Cell Biol. 2007; 27(7):2442-51. PMC: 1899895. DOI: 10.1128/MCB.01570-06. View

Rose J, Yurchak A, Jusko W . Dose dependent pharmacokinetics of prednisone and prednisolone in man. J Pharmacokinet Biopharm. 1981; 9(4):389-417. DOI: 10.1007/BF01060885. View

Rosewicz S, Logsdon C . Glucocorticoids stimulate ornithine decarboxylase gene expression in pancreatic AR42J cells. Gastroenterology. 1991; 101(4):1102-8. DOI: 10.1016/0016-5085(91)90740-c. View

Russcher H, Smit P, van den Akker E, van Rossum E, Brinkmann A, de Jong F . Two polymorphisms in the glucocorticoid receptor gene directly affect glucocorticoid-regulated gene expression. J Clin Endocrinol Metab. 2005; 90(10):5804-10. DOI: 10.1210/jc.2005-0646. View

Hirano T, Oka K, Takeuchi H, Sakurai E, Kozaki K, Matsuno N . A comparison of prednisolone and methylprednisolone for renal transplantation. Clin Transplant. 2000; 14(4 Pt 1):323-8. DOI: 10.1034/j.1399-0012.2000.140408.x. View

Yang J, Liu J, DeFranco D . Subnuclear trafficking of glucocorticoid receptors in vitro: chromatin recycling and nuclear export. J Cell Biol. 1997; 137(3):523-38. PMC: 2139874. DOI: 10.1083/jcb.137.3.523. View

Necela B, Cidlowski J . Development of a flow cytometric assay to study glucocorticoid receptor-mediated gene activation in living cells. Steroids. 2003; 68(4):341-50. DOI: 10.1016/s0039-128x(03)00032-1. View

Novotna A, Pavek P, Dvorak Z . Construction and characterization of a reporter gene cell line for assessment of human glucocorticoid receptor activation. Eur J Pharm Sci. 2012; 47(5):842-7. DOI: 10.1016/j.ejps.2012.10.003. View

10.

Echeverria P, Mazaira G, Erlejman A, Gomez-Sanchez C, Piwien Pilipuk G, Galigniana M . Nuclear import of the glucocorticoid receptor-hsp90 complex through the nuclear pore complex is mediated by its interaction with Nup62 and importin beta. Mol Cell Biol. 2009; 29(17):4788-97. PMC: 2725705. DOI: 10.1128/MCB.00649-09. View

11.

Jaffuel D, Roumestan C, Balaguer P, Henriquet C, Gougat C, Bousquet J . Correlation between different gene expression assays designed to measure trans-activation potencies of systemic glucocorticoids. Steroids. 2001; 66(7):597-604. DOI: 10.1016/s0039-128x(00)00235-x. View

12.

Rupprecht R, Reul J, van Steensel B, Spengler D, Soder M, Berning B . Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligands. Eur J Pharmacol. 1993; 247(2):145-54. DOI: 10.1016/0922-4106(93)90072-h. View

13.

Sedlak D, Paguio A, Bartunek P . Two panels of steroid receptor luciferase reporter cell lines for compound profiling. Comb Chem High Throughput Screen. 2011; 14(4):248-66. PMC: 3234597. DOI: 10.2174/138620711795222446. View

14.

Heitzer M, Wolf I, Sanchez E, Witchel S, DeFranco D . Glucocorticoid receptor physiology. Rev Endocr Metab Disord. 2007; 8(4):321-30. DOI: 10.1007/s11154-007-9059-8. View

15.

Meijsing S, Pufall M, So A, Bates D, Chen L, Yamamoto K . DNA binding site sequence directs glucocorticoid receptor structure and activity. Science. 2009; 324(5925):407-10. PMC: 2777810. DOI: 10.1126/science.1164265. View

16.

Zitnik R, Whiting N, Elias J . Glucocorticoid inhibition of interleukin-1-induced interleukin-6 production by human lung fibroblasts: evidence for transcriptional and post-transcriptional regulatory mechanisms. Am J Respir Cell Mol Biol. 1994; 10(6):643-50. DOI: 10.1165/ajrcmb.10.6.7516173. View

17.

Frank F, Ortlund E, Liu X . Structural insights into glucocorticoid receptor function. Biochem Soc Trans. 2021; 49(5):2333-2343. PMC: 9274455. DOI: 10.1042/BST20210419. View

18.

Schaaf M, Lewis-Tuffin L, Cidlowski J . Ligand-selective targeting of the glucocorticoid receptor to nuclear subdomains is associated with decreased receptor mobility. Mol Endocrinol. 2005; 19(6):1501-15. DOI: 10.1210/me.2005-0050. View

19.

Orti E, Mendel D, Smith L, Bodwell J, Munck A . A dynamic model of glucocorticoid receptor phosphorylation and cycling in intact cells. J Steroid Biochem. 1989; 34(1-6):85-96. DOI: 10.1016/0022-4731(89)90069-1. View

20.

Smit P, Russcher H, de Jong F, Brinkmann A, Lamberts S, Koper J . Differential regulation of synthetic glucocorticoids on gene expression levels of glucocorticoid-induced leucine zipper and interleukin-2. J Clin Endocrinol Metab. 2005; 90(5):2994-3000. DOI: 10.1210/jc.2004-2298. View