Abstract
A fourth-generation pharmacokinetic/pharmacodynamic (PK/PD) model for receptor/genemediated effects of corticosteroids was developed. Male adrenalectomized Wistar rats received a 50 mg/kg iv bolus dose of methylprednisolone (MPL). Plasma concentrations of MPL, hepatic glucocorticoid receptor (GR) messenger RNA (mRNA) and GR density, tyrosine aminotransferase (TAT) mRNA, and TAT activity in liver were determined at various time points up to 72 hr after MPL dosing. Down-regulation of GR mRNA and GR density were observed: GR mRNA level declined to 45–50% of the baseline in 8–10 hr, and slowly returned to predose level in about 3 days; GR density fell to 0 soon after dosing and returned to the baseline in two phases. The first phase, occurring in the first 10 hr, entailed recovery from 0 to 30%. The second phase was parallel to the GR mRNA recovery phase. Two indirect response models were applied for GR mRNA dynamics regulated by activated steroid-receptor complex. A full PK/PD model for GR mRNA/GR down-regulation was proposed, including GR recycling theory. TAT mRNA began to increase at about 1.5 hr, reached the maximum at about 5.5 hr, and declined to the baseline at about 14 hr after MPL dosing. TAT induction followed a similar pattern with a delay of about 1–2 hr. A transcription compartment was applied as one of the cascade events leading to TAT mRNA and TAT induction. Pharmacodynamic parameters were obtained by fitting seven differential equations piecewise using the maximum likelihood method in the ADAPT II program. This model can describe GR down-regulation and the precursor/product relationship between TAT mRNA and TAT in receptor/gene-mediated corticosteroid effects.
Similar content being viewed by others
REFERENCES
K. H. Lew and W. J. Jusko. Pharmacodynamic modeling for cortisol suppression from fluocortolone. Eur. J. Clin. Pharmacol. 45:581–583 (1993).
L. E. Fisher, E. A. Ludwig, and W. J. Jusko. Pharmacoimmunodynamics of methylprednisolone: trafficking of helper-T lymphocytes. J. Pharmacokin. Biopharm. 20:319–331 (1992).
M. A. Milad, E. A. Ludwig, A. Anne, E. Middleton Jr., and W. J. Jusko. Pharmacodynamic model for joint exogenous and endogenous corticosteroid suppression of lymphocyte trafficking. J. Pharmacokin. Biopharm. 22:469–480 (1994).
J. A. Wald, D. E. Salazar, H. Cheng, and W. J. Jusko. Two-compartment basophil cell trafficking model for methylprednisolone pharmacodynamics. J. Pharmacokin. Biopharm. 19:521–536 (1991).
K. H. Lew, E. A. Ludwig, M. A. Milad, K. Donovan, E. Middleton Jr., J. J. Ferry, and W. J. Jusko. Gender-based effect on methylprednisolone pharmacokinetics and pharmacodynamics. Clin. Pharmacol. Ther. 54:402–414 (1993).
R. I. Scheinman, P. C. Cogswell, A. K. Lofquist, and A. S. Baldwin Jr. Roles of transcriptional activation of IκBα in mediation of immunosuppression by glucocorticoids. Science 270:283–286 (1995).
N. Auphan, J. A. DiDonato, C. Rosette, A. Helmberg, and M. Karin. Immunosuppression by glucocorticoids: Inhibition of NF-κB activity through induction of IκB synthesis. Science 270:286–290 (1995).
T. Seene. Turnover of skeletal muscle contractile proteins in glucocorticoid myopathy. J. Steroid Biochem. Biol. 50:1–4 (1994).
P. J. Evans. The regulation of hepatic tyrosine aminotransferase. Biochim. Biophys. Acta 677:433–444 (1981).
M. Izawa, A. Yosida, S. Ichii. Dynamics of glucocorticosteroid receptor and induction of tyrosine aminotransferase in rat liver. Endocrinol Japan 29:209–218 (1982).
A. I. Nichols and W. J. Jusko. Receptor mediated prednisolone pharmacodynamics in rat: Model verification using a dose-sparing regimen. J. Pharmacokin. Biopharm. 18:189–208 (1990).
F. D. Boudinot, R. D'Ambrosio, and W. J. Jusko. Receptor-mediated pharmacodynamics of prednisolone in the rat. J. Pharmacokin. Biopharm. 14:469–493 (1986).
A. I. Nichols, F. D. Boudinot, and W. J. Jusko. Second generation model for prednisolone pharmacodynamics in the rat. J. Pharmacokin. Biopharm. 17:209–227 (1989).
D. B. Haughey and W. J. Jusko. Receptor-mediated methylprednisolone pharmacodynamics in rats: steroid-induced receptor down-regulation. J. Pharmacokin. Biopharm. 19:333–355 (1992).
D. C. DuBois, R. R. Almon, and W. J. Jusko. Molar quantification of specific messenger ribonucleic acid expression in Northern hybridization using cRNA standards. Anal. Biochem. 210:140–144 (1993).
Z-X. Xu, Y-N. Sun, D. C. DuBois, R. R. Almon, and W. J. Jusko. Third-generation model for corticosteroid pharmacodynamics: Roles of glucocorticoid receptor mRNA and tyrosine aminotransferase mRNA in rat liver. J. Pharmacokin. Biopharm. 23:163–181 (1995).
N. L. Dayneka, V. Garg, and W. J. Jusko. Comparison of four basic models of indirect pharmacodynamic responses. J. Pharmacokin. Biopharm. 21:457–478 (1993).
R. M. Oakley and J. A. Cidlowski. Homologous down regulation of the glucocorticoid receptor: The molecular machinery. Crit. Rev. Eukary. Gen. Expr. 3:63–88 (1993).
D. W. Tingley. Evolutions: steroid-hormone receptor signaling. J. NIH Res. 8:81–88 (1996).
N. O. Vamvakopoulos. Tissue-specific expression of heat shock proteins 70 and 90: potential implication for differential sensitivity of tissues to glucocorticoids. Mol. Cell. Endocrinol. 98:49–54 (1993).
E. V. Mishina, R. M. Straubinger, N. A. Pyszczynski, and W. J. Jusko. Enhancement of tissue delivery and receptor occupancy of methylprednisolone in rats by a liposomal formulation. Pharm. Res. 10:1402–1410 (1993).
M. J. Czar, J. K. Owens-Grillo, K. D. Dittmar, K. A. Hutchison, A. M. Zacharek, K. L. Leach, M. R. Deibel Jr., and W. B. Pratt. Characterization of the protein-protein interactions determining the shock protein (hsp 90.hsp 70.hsp 56) heterocomplex. J. Biol. Chem. 269:11155–11161 (1994).
E. Orti, L. M. Hu, and A. Munck. Kinetics of glucocorticoid receptor phosphorylation in intact cells. Evidence for hormone-induced hyperphosphorylation after activation and recycling of hyperphosphorylated receptors. J. Biol. Chem. 268:7779–7784 (1993).
I. Segard-Maurel, K. Rajkowski, N. Jibard, G. Schweizer-Groyer, E-E. Baulieu, and F. Cadepond. Glucocorticoid receptor dimerization investigated by analysis of receptor binding to glucocorticosteroid responsive elements using a monomer-dimer equilibrium model. Biochemistry 35:1634–1642 (1996).
A. J. Cooney, and S. Y. Tsai. Nuclear receptor-DNA interactions. In M-J. Tsai and B. W. O'Malley (eds.), Mechanism of Steroid Hormone Regulation of Gene Transcription, R. G. Landes, 1994, pp. 25–59.
B. Lewin. Regulation of transcription: factors that activate the basal apparatus. In Genes, V, Oxford University Press, 1994, pp. 879–909.
B. Lewin. Control at initiation: RNA polymerase-promoter interactions. In Genes V, Oxford University Press, 1994, pp. 377–411.
B. Lewin. The assembly line for protein synthesis. In Genes V, Oxford University Press, 1994, pp. 163–195.
Y. Dong, L. Poellinger, J-A. Gustafsson, and S. Okret. Regulation of glucocorticoid receptor expression: Evidence for transcriptional and posttranslational mechanism. Mol. Endocrinol. 2:1256–1264 (1988).
W. V. Vedeckis, M. Ali, and H. R. Allen. Regulation of glucocorticoid receptor protein and mRNA levels. Cancer Res. (Suppl.) 49:2295s–2320s (1989).
P. Bernstein, S. W. Peltz, and J. Ross. The poly(A)—poly(A)-binding protein complex is a major determination of mRNA stability in vitro. Mol. Cell Biol. 9:659–670 (1989).
J. S. Malter. Identification of a AUUUA-specific messenger RNA binding protein. Science 246:664–666 (1989).
B. Z. Carter and J. S. Malter. Biology of disease. Regulation of mRNA stability and its relevance to disease. Lab. Invest. 65:610–621 (1991).
A. Munck and N. J. Holbrook. Glucocorticoid-receptor complexes in rat thymus cells: Rapid kinetic behavior and a cyclic model. J. Biol. Chem. 259:820–831 (1984).
W. F. Ebling, S. J. Szefler, and W. J. Jusko. Methylprednisolone disposition in rabbits: analysis, prodrug conversion, reversible metabolism and comparison with man. Drug Metab. Dispos. 13:296–304 (1985).
O. M. Lowry, N. J. Rosebrough, A. L. Farr, and R. J. Randall. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193:265–272 (1951).
J. M. Chirgwin, A. E. Przybyla, R. J. MacDonald, and W. J. Rutter. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 18:5294–5299 (1979).
P. A. Kreig and D. A. Melton. In vitro RNA synthesis with SP6 RNA polymerase. Meth. Enzymol. 155:397–415 (1987).
D. C. DuBois, Z-X. Xu, L. McKay, R. R. Almon, N. Pyszczynski, and W. J. Jusko. Differential dynamics of receptor down-regulation and tyrosine aminotransferase induction following glucocorticoid treatment. J. Steroid Biochem. Mol. Biol. 54:237–243 (1995).
J. P. Northrop, M. Danielsen, and G. M. Ringold. Analysis of glucocorticoid unresponsive cell variants using a mouse glucocorticoid receptor complementary DNA clone. J. Biol. Chem. 261:11064–11070 (1986).
T. I. Diamondstone. Assay of tyrosine aminotransferase activity by conversion of p-hydroxyphenylpyruvate to p-hydroxybenzaldehyde. Anal. Biochem. 16:395–401 (1966).
L. Z. Benet and R. L. Galeazzi. Noncompartmental determination of the steady-state volume of distribution. J. Pharm. Sci. 68:1071–1074 (1979).
C. C. Peck, S. L. Beal, L. B. Sheiner, and A. I. Nichols. Extended least squares nonlinear regression: A possible solution to the “choice of weights” problem in analysis of individual pharmacokinetic data. J. Pharmacokin. Biopharm. 12:545–558 (1984).
D. Z. D'Argenio and A. Schumitzky. ADAPT II Program Menu: Pharmacokinetic/Pharmacodynamic Systems Analysis. Biomedical Simulation Resource, Los Angeles, CA, 1997.
G. P. Lewis, W. J. Jusko, C. W. Burke, L. Graves, and the Boston Collaborative Drug Surveillance Program, Prednisone side-effects and serum-protein level: A collaborative study. Lancet 2:778–781 (1971).
J. Q. Rose, A. M. Yurchak, and W. J. Jusko. Dose dependent pharmacokinetics of prednisone and prednisolone in man. J. Pharmacokin. Biopharm. 9:389–417 (1981).
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).
W. F. Ebling, R. L. Milsap, S. J. Szefler, and W. J. Jusko. 6α-methylprednisolone and 6α-methylprednisolone plasma protein binding in humans and rabbits. J. Pharm. Sci. 75:760–763 (1986).
D. B. Haughey. Dose-dependent pharmacokinetics and receptor-mediated pharmacodynamics of methylprednisolone in the rat. Ph.D. dissertation, SUNY at Buffalo, 1990.
D. B. Haughey and W. J. Jusko. Reversible metabolism and nonlinear disposition of methylprednisolone in the rat. Pharm. Res. 6:S181 (1990). (Abstract.)
S. Okret, L. Poellinger, Y. Dong, and J-Å. Gustafsson. Down-regulation of glucocorticoid receptor mRNA by glucocorticoid hormones and recognition by the receptor of a specific binding sequence within a receptor cDNA clone. Proc. Natl. Acad. Sci. U.S. 83:5899–5903 (1986).
W. R. McIntyre and H. H. Samuels. Triamcinolone acetonide regulates glucocorticoid-receptor levels by decreasing the half-life of the activated nuclear-receptor form. J. Biol. Chem. 260:418–427 (1985).
K. L. Burnstein, C. M. Jewell, and J. A. Cidlowski. Human glucocorticoid receptor cDNA contains sequences sufficient for receptor down-regulation. J. Biol. Chem. 265:7284–7291 (1990).
W. Hoeck, S. Rusconi, and B. Groner. Down-regulation and phosphorylation of glucocorticoid receptors in cultured cells. Investigations with a monospecific antiserum against a bacterially expressed receptor fragment. J. Biol. Chem. 264:14396–14402 (1989).
J. L. Hargrove and F. H. Schmidt. The roles of mRNA and protein stability in gene expression. FASEB J. 3:2360–2370 (1989).
E. W. Müllner and L. C. Kühn. Stem-loop in the 3′ untranslated region mediates iron-dependent regulation of transferrin receptor mRNA stability in the cytoplasm. Cell 53:815–825 (1988).
L. B. Sheiner, D. R. Stanski, S. Vozeh, R. D. Miller, and J. Ham. Simultaneous modeling of pharmacokinetics and pharmacodynamics: Application to d-tubocurarine. Clin. Pharmacol. Ther. 25:358–371 (1979).
H. M. Westphal, G. Moldenhauer, and M. Beato. Monoclonal antibodies to the rat liver glucocorticoid receptor. EMBO J. 1:1467–1471 (1982).
J. J. Pink and V. C. Jordan. Models of estrogen receptor regulation by estrogens and antiestrogens in breast cancer cell lines. Cancer Res. 56:2321–2330 (1996).
J. B. Levy, T. M. Seay, D. J. Tindall, and D. A. Husmann. The effects of androgen administration on phallic androgen receptor. J. Urol. 156:775–779 (1996).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Sun, YN., DuBois, D.C., Almon, R.R. et al. Fourth-Generation Model for Corticosteroid Pharmacodynamics: A Model for Methylprednisolone Effects on Receptor/Gene-Mediated Glucocorticoid Receptor Down-Regulation and Tyrosine Aminotransferase Induction in Rat Liver. J Pharmacokinet Pharmacodyn 26, 289–317 (1998). https://doi.org/10.1023/A:1023233409550
Published:
Issue Date:
DOI: https://doi.org/10.1023/A:1023233409550