Skip to main content
Log in

Receptor-mediated pharmacodynamics of prednisolone in the rat

  • Published:
Journal of Pharmacokinetics and Biopharmaceutics Aims and scope Submit manuscript

Abstract

A phartnacokinetic/pharmacodynamic model describing receptor-mediated effects of prednisolone is presented. The basis of the model is the generally accepted mechanism of action of steroid hormones in which corticosteroids bind to cytosolic receptors forming steroid-receptor complexes, which are activated and translocated into the nucleus. There the complexes associate with specific DNA sequences and modulate the rate of transcription of DNA into specific RNAs that code for the synthesis of proteins that elicit biological responses. Prednisolone, 5 or 50 mg/kg, was administered intravenously to adrenalectomized rats. Total plasma, free plasma, CBG-free plasma, and liver prednisolone concentrations were measured simultaneously with free hepatic cytosolic glucocorticoid receptor concentrations and tyrosine aminotransferase (TAT) activity of the liver as a function of time. The association/dissociation kinetics of prednisolone binding to the glucocorticoid receptor were measured separately in vitroat 37°C. Total plasma, free plasma, and CBG-free plasma prednisolone concentrations could be used equally well in the model to account for the time course of receptor concentrations and TAT activity. However, use of liver steroid concentrations resulted in an overestimation of receptor depletion. Steroid concentrations in plasma increased 20 to 30-fold with a tenfold increase in dose, but receptor occupancy and TAT activity over time increased about threefold. While prednisolone pharmacokinetics were dose-dependent, parameters describing receptor kinetics and TAT activity were constant at each prednisolone dose. The major determinants of receptor-mediated glucocorticoid activity are confirmed to be the availability of the receptor, drug-receptor dissociation rate, and corticosteroid persistence in the biophase.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. G. Levy. Kinetics of pharmacologic effects.Clin. Pharmacol. Ther. 7:362–372 (1966).

    CAS  PubMed  Google Scholar 

  2. E. J. Ariens. Drug levels in the target tissue and effect.Clin. Pharmacol. Ther. 16:155–175 (1974).

    CAS  PubMed  Google Scholar 

  3. N. H. G. Holford and L. B. Sheiner. Pharmacokinetic and pharmacodynamic modelingin vivo.CRC Crit. Rev. Bioeng. 5:273–322 (1981).

    CAS  Google Scholar 

  4. B. Oosterhuis. R. J. M. Ten Berge, H. P. Sauerwein, E. Endert, P. T. A. Schellekens, and C. J. Van Boxtel. Pharmacokinetic-pharmacodynamic modeling of prednisolone induced lymphocytopenia in man.J. Pharmacol. Exp. Ther. 229:539–545 (1984).

    CAS  PubMed  Google Scholar 

  5. L. K. Paalzow. Integrated pharmacokinetic-pharmacodynamic modeling of drugs acting on the CNS.Metab. Rev. 15:383–400 (1984).

    Article  Google Scholar 

  6. M. L. Jack, W. A. Colburn, N. M. Spirt, G. Bautz, M. Zanko, W. D. Horst, and R. A. O'Brien. A pharmacokinetic/pharmacodynamic/receptor binding model to predict the onset and duration of pharmacological activity of the benzodiazepines.Prog. Neuropsychopharmacol. Biol. Psychiat. 7:629–635 (1983).

    Article  CAS  Google Scholar 

  7. E. V. Jenson and H. I. Jacobson. Basic guides to the mechanism of estrogen action.Recent Prog. Horm. Res. 18:387–414 (1962).

    Google Scholar 

  8. J. D. Baxter and J. W. Funder. Hormone receptors.N. Engl. J. Med. 301:1149–1161 (1979).

    Article  CAS  PubMed  Google Scholar 

  9. A. Munck and K. Leung. In J. R. Pasqualini (ed.),Glucocorticoid Receptors and Mechanism of Action of Steroid Hormones, Marcel Dekker, New York, 1977, pp. 311–397.

    Google Scholar 

  10. M. Izawa, A. Yoshida, and S. Ichii. Dynamics of glucocorticoid receptor and induction of tyrosine aminotransferase in rat liver.Endocrinol. Japon. 29:209–218 (1982).

    Article  CAS  Google Scholar 

  11. T. J. Schmidt and G. Litwack. Activation of the glucocorticoid-receptor complex.Physiol. Rev. 62:1131–1192 (1982).

    CAS  PubMed  Google Scholar 

  12. G. G. Rousseau. Control of gene expression by glucocorticoid hormones.Biol. Chem. J. 225:1–12 (1984).

    Google Scholar 

  13. G. J. Blackwell, R. Carnuccio, M. DiRosa, R. J. Flower, L. Parente, and P. Pessico. Macrocortin: A polypeptide causing anti-phospholipase effect of glucocorticoids.Nature 287:147–149 (1980).

    Article  CAS  PubMed  Google Scholar 

  14. P. L. Ballard, J. D. Baxter, S. J. Higgins, G. G. Rousseau, and G. M. Tomkins. General presence of glucocorticoid receptors in mammalian tissues.Endocrinology 94:998–1002 (1974).

    Article  CAS  PubMed  Google Scholar 

  15. A. M. P. Saaverdra-Delgrado, K. P. Mathews, P. M. Pan, D. R. Kay, and M. L. Mulenberg. Dose response studies of the suppression of whole blood histamine and basophil counts of prednisone.J. Allergy Clin. Immunol. 66:464–471 (1980).

    Article  Google Scholar 

  16. R. Ellul-Micallef and F. F. Fenech. Intravenous prednisolone in chronic bronchial asthma.Thorax 30:312–315 (1975).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. H. Kitagawa, T. Mohri, and M. Kitagawa. Comparative studies on anti-inflammatory effect and biological fates of 21-phosphates and -sulfates of dexamethasone and prednisolone,Arzneim. Forsch. 22:402–410 (1972).

    CAS  Google Scholar 

  18. M. Kalimi, M. Beato, and P. Feigelson. Interaction of glucocorticoids with rat liver nuclei. I. Role of the cytosol proteins.Biochemistry 12:3365–3371 (1973).

    Article  CAS  PubMed  Google Scholar 

  19. C. R. Wira and A. Munck. Glucocorticoid-receptor complexes in rat thymus cells.J. Biol. Chem. 249:5328–5336 (1974).

    CAS  PubMed  Google Scholar 

  20. F. Payvar, O. Wrange, J. Carlstedt-Duke, S. Okret, J.-A. Gustafsson, and K. R. Yamamoto. Purified glucocorticoid receptors binding selectivelyin vitro to a cloned DNA fragment whose transcription is regulated by glucocorticoidsin vivo.Proc. Natl. Acad. Sci. USA 78:6628–6632 (1981).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. M. Pfahl. Specific binding of the glucocorticoid-receptor complex to the mouse mammary tumor proviral promotor region.Cell 31:475–482 (1982).

    Article  CAS  PubMed  Google Scholar 

  22. B. M. Raaka and H. H. Samuels. The glucocorticoid receptor in GH1 cells.J. Biol. Chem. 258:417–425 (1983).

    CAS  PubMed  Google Scholar 

  23. S. Miyabe and R. W. Harrison.In vivo activation and nuclear binding of the ALT-20 mouse pituitary tumor cell glucocorticoid receptor.Endocrinology 112:2174–2180 (1983).

    Article  CAS  PubMed  Google Scholar 

  24. J. M. Nickol, K.-L. Lee, and F. T. Kenney. Changes in hepatic levels of tyrosine aminotransferase messenger RNA during induction by hydrocortisone.J. Biol. Chem. 253:4009–4015 (1978).

    CAS  PubMed  Google Scholar 

  25. D. Granner, P. Olson, S. Seifert, C. Block, M. Diesterhaft, J. Hargrove, and T. Noguchi. Regulation of tyrosine aminotransferase mRNA in HTC cells.Ann. N. Y. Acad. Sci. 349:183–194 (1980).

    Article  CAS  PubMed  Google Scholar 

  26. J. Q. Rose and W. J. Jusko. Corticosteroid analysis in biological fluids by high-performance liquid chromatography.J. Chromatogr. 162:273–280 (1979).

    Article  CAS  PubMed  Google Scholar 

  27. N. Khalafallah and W. J. Jusko. Tissue distribution of prednisolone in the rabbit.J. Pharmacol. Exp. Ther. 229:719–725 (1984).

    CAS  PubMed  Google Scholar 

  28. F. D. Boudinot and W. J. Jusko. Fluid shifts and other factors affecting plasma protein binding of prednisolone by equilibrium dialysis.J. Pharm. Sci. 73:774–780 (1984).

    Article  CAS  PubMed  Google Scholar 

  29. R. L. Priore and H. E. Rosenthal. A statistical method for the estimation of binding parameters in a complex system.Anal. Biochem. 70:231–240 (1976).

    Article  CAS  PubMed  Google Scholar 

  30. Packard Instrument Co., Instrument Manual 2136, Downers Grove, Illinois (1977).

    Google Scholar 

  31. N. Lui, R. R. Almon, and W. J. Jusko. Comparison of filtration and equilibrium dialysis methods for3H-imipramine binding to human platelets.Anal. Biochem. 139:42–57 (1984).

    Article  CAS  PubMed  Google Scholar 

  32. C. M. Metzler, G. K. Elfring, and A. J. McEwen. A package of computer programs for pharmacokinetic modeling.Biometrics 30:562–563 (1974).

    Article  Google Scholar 

  33. T. I. Diamondstone. Assay of tyrosine transaminase activity by conversion ofp-hyroxyphenylpyruvate top-hydroxybenzaldehyde.Anal. Biochem. 16:395–401 (1966).

    Article  CAS  Google Scholar 

  34. O. M. Lowry, N. J. Rosebrough, A. L. Farr, and R. J. Randal. Protein measurement with the folin phenol reagent.J. Biol. Chem. 193:265–272 (1951).

    CAS  PubMed  Google Scholar 

  35. F. D. Boudinot and W. J. Jusko. Dose dependent pharmacokinetics of prednisolone in normal and adrenalectomized rats.J. Pharmacokin. Biopharm. 14:453–467 (1986).

    Article  CAS  Google Scholar 

  36. P. G. W. Plageman and J. Erbe. Glucocorticoids-uptake by simple diffusion by cultured Reuber and Novikoff rat hepatoma cells.Biochem. Pharmacol. 25:1489–1494 (1976).

    Article  Google Scholar 

  37. W. M. Pardridge and L. J. Mietus. Transport of protein-bound steroid hormones into liverin vivo.Am. J. Physiol. 237:E367-E372 (1979).

    CAS  PubMed  Google Scholar 

  38. S. R. Gross, L. Aronow, and W. B. Pratt. The active transport of cortisol of mouse fibroblasts growingin vitro.J. Cell. Biol. 44:103–114 (1970).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. M. L. Rao, G. S. Rao, M. Holler, H. Breuer, P. J. Schattenberg, and W. D. Stein. Uptake of cortisol by isolated rat liver cells. A phenomenon indicative of carrier-mediation and simple diffusion.J. Physiol. Chem. 357:573–584 (1976).

    Article  CAS  Google Scholar 

  40. J. F. Hackney, S. R. Gross, L. Aronow, and W. B. Pratt. Specific glucocorticoid-binding macromolecules from mouse fibroblasts growingin vitro.Mol. Pharmacol. 6:500–512 (1970).

    CAS  PubMed  Google Scholar 

  41. N. Khalafallah and W. J. Jusko. Determination and prediction of tissue binding of prednisolone in the rabbit.J. Pharm. Sci. 73:362–366 (1984).

    Article  CAS  PubMed  Google Scholar 

  42. M. Mayer, N. Kaiser, R. J. Millholland, and F. Rosen. Cortisol binding in rat skeletal muscle.J. Biol. Chem. 250:1207–1210 (1975).

    CAS  PubMed  Google Scholar 

  43. W. R. Slaunwhite, G. M. Lockie, N. Back, and A. A. Sandberg. Inactivityin vivo of transcortin bound cortisol.Science 135:1062–1063 (1962).

    Article  CAS  PubMed  Google Scholar 

  44. A. Kawai and F. E. Yates. Interference with feedback inhibition of adrenocorticotropin release by protein binding of corticosterone.Endocrinology 79:1040–1046 (1965).

    Article  Google Scholar 

  45. B. Koch, B. Lutz, G. Schmitt, and C. Mailhe. Influence of transcortin on degradation and tissue uptake of corticosterone in the infant rat.Horm. Metab. Res. 2:292–297 (1970).

    Article  CAS  PubMed  Google Scholar 

  46. M. Lippman and E. B. Thompson. The role of transcription in glucocorticoid mediated enzyme induction: Tyrosine aminotransferase induction in hepatoma tissue culture cells.J. Steroid Biochem. 5:461–465 (1974).

    Article  CAS  PubMed  Google Scholar 

  47. W. Rosner. Recent studies on the binding of cortisol in serum.J. Steroid Biochem. 3:531–542 (1972).

    Article  CAS  PubMed  Google Scholar 

  48. G. P. Lewis, W. J. Jusko, C. W. Burke, and L. Graves. Prednisolone side-effects and serum protein levels.Lancet 2:778–781 (1971).

    Article  CAS  PubMed  Google Scholar 

  49. P. L. Ballard. Delivery and transport of glucocorticoids to target cells.Monogr. Endocrinol. 12:25–48 (1971).

    Article  Google Scholar 

  50. A. Munck and T. Brink-Johnsen. Specific and nonspecific physiochemical interactions of glucocorticoids and related steroids with rat thymus cellsin vitro.J. Biol. Chem. 243:5556–5565 (1968).

    CAS  PubMed  Google Scholar 

  51. E. Bloom, D. T. Matulich, N. C. Lan, S. J. Higgins, S. S. Simons, and J. D. Baxter. Nuclear binding of glucocorticoid receptors: Relations between cytosol binding, activation and the biological response.J. Steroid Biochem. 12:175–184 (1980).

    Article  CAS  PubMed  Google Scholar 

  52. A. Munck and W. J. Holbrook. Glucocorticoid-receptor complexes in rat thymus cells.J. Biol. Chem. 259:820–831 (1984).

    CAS  PubMed  Google Scholar 

  53. P. A. Bell and A. Munck. Steroid-binding properties and stabilization of cytoplasmic glucocorticoid receptors from rat thymus cells.Biochem. J. 136:97–107 (1973).

    CAS  PubMed Central  PubMed  Google Scholar 

  54. J. A. Goidl, M. H. Cake, K. P. Dolan, L. G. Parchman, and G. Litwack. Activation of the rat liver glucocorticoid-receptor complex.Biochemistry 16:2125–2130 (1977).

    Article  CAS  PubMed  Google Scholar 

  55. H. M. Westphal and M. Beato. The activated glucocorticoid receptor of rat liver.Eur. J. Biochem. 106:395–403 (1980).

    Article  CAS  PubMed  Google Scholar 

  56. M. Koblinsky, M. Beato, M. Kalimi, and P. Feigelson. Glucocorticoid binding proteins of rat liver cytosol. II. Physical characterization and properties of the binding proteins.J. Biol. Chem. 247:7897–7904 (1972).

    CAS  PubMed  Google Scholar 

  57. A. Munck, C. Wira, D. A. Young, K. M. Mosher, C. Hallahan, and P. A. Bell. Glucocorticoid-receptor complexes and the earliest steps in the action of glucocorticoids on thymus cells.J. Steroid Biochem. 3:567–578 (1972).

    Article  CAS  PubMed  Google Scholar 

  58. J. L. Middlebrook, M. D. Wong, D. N. Ishii, and L. Aronow. Subcellular distribution of glucocorticoid receptors in mouse fibroblasts.Biochemistry 14:180–186 (1975).

    Article  CAS  PubMed  Google Scholar 

  59. M. Izawa, Y. Satoh, and S. Ichii. Recycling of steroid hormones. In H. Imura and H. Kuzuya (eds.),Hormone Receptors and Receptor Diseases, Excerpta Medica, Amsterdam, 1983, pp. 127–135.

    Google Scholar 

  60. W. R. McIntyre and H. H. Samuels. Triamcinolone acetonide regulates glucocorticoidreceptor levels by decreasing the half-life of the activated nuclear-receptor form.J. Biol. Chem. 260:418–427 (1985).

    CAS  PubMed  Google Scholar 

  61. F. D. Boudinot. The role of protein binding in prednisolone pharmacodynamics. Ph.D. thesis, State University of New York at Buffalo (1986).

    Google Scholar 

  62. H. G. Morris. Mechanisms of action and therapeutic role of corticosteroids in asthma.J. Allergy Clin. Immunol. 75:1–13 (1985).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Additional information

Supported in part by grant GM 24211 from the National Institutes of General Medical Sciences, NIH.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Boudinot, F.D., D'Ambrosio, R. & Jusko, W.J. Receptor-mediated pharmacodynamics of prednisolone in the rat. Journal of Pharmacokinetics and Biopharmaceutics 14, 469–493 (1986). https://doi.org/10.1007/BF01059656

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01059656

Key words

Navigation