Abstract
Dose-dependent and repeated-dose effects of methylprednisolone (MPL) on down-regulation of glucocorticoid receptor messenger RNA (GR mRNA) and GR density, as well as tyrosine aminotransferase (TAT) mRNA and TAT induction by receptor/gene-mediated mechanisms in rat liver were examined. A previously developed pharmacokinetic/pharmacodynamic (PK/PD) model was used to design these studies which sought to challenge the model. Three groups of male adrenalectomized Wistar rats received MPL by iv injection: low-dose (10 mg/kg at Time 0), high-dose (50 mg/kg at Time 0), and dual-dose (50 mg/kg at Time 0 and 24 hr). Plasma concentrations of MPL, and hepatic content of free GR, GR mRNA, TAT mRNA, and TAT activity were determined. The P-Pharm program was applied for population analysis of MPL PK revealing low interindividual variation in CL and Vc values (3–14%). Two indirect response models were applied to test two competing hypotheses for GR mRNA dynamics. Indirect Pharmacodynamic Response Model I (Model A) where the complex in the nucleus decreases the transcription rate of GR mRNA better described GR mRNA/GR down-regulation. Levels of TAT mRNA began to increase at 1–2 hr, reached a maximum at 5–6 hr, and declined to the baseline at 12–14 hr after MPL dosing. The induction of TAT activity followed a similar pattern with a delay of about 1–2 hr. The low-dose group had 50–60% of the TAT mRNA and TAT induction compared to the high-dose group. Since the GR density returned to about 70% of the baseline level before the second 50 mg/kg dose at 24 hr, tolerance was found for TAT mRNA/TAT induction where only 50–60% of the initial responses were produced. Our fourth-generation model describes the dose dependence and tolerance effects of TAT mRNA/TAT induction by MPL involving multiple-step signal transduction controlled by the steroid regimen, free GR density, and GR occupancy. This model may provide the foundation for studying other induced proteins or enzymes mediated by the similar receptor/nuclear events.
Similar content being viewed by others
REFERENCES
A. C. Guyton. The adrenocortical hormones. In Textbook of Medical Physiology, W. B. Saunders, 1986, pp. 909–922.
B. P. Schimmer and K. L. Parker. Chapter 59: Adrenocorticotropic hormones; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones. In J. G. Hardman, L. E. Limbird, P. B. Molinoff, R. W. Ruddon, and A. G. Gilman (eds.), Goodman & Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, 1996, pp. 1459–1485.
D. T. Boumpas, G. P. Chrousos, R. L. Wilder, T. R. Cupps, and J. E. Balow. Glucocorticoid therapy for immuno-mediated diseases: Basic and clinical correlates. Ann. Intern. Med. 119:1198–1208 (1993).
S. L. Swartz and R. G. Dluhy. Corticosteroids: Clinical pharmacology and therapeutic use. Drugs 16:238–255 (1978).
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).
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 IκBα synthesis. Science 270:286–290 (1995).
S. R. Max, J. Mill, K. Mearow, M. Konagaya, Y. Konagaya, J. W. Thomas, C. Banner, and L. Vitkovi. Dexamethasone regulates glutamine synthetase expression in rat skeletal muscle. Am. J. Physiol. 255:E397–E408 (1988).
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. 20:333–355 (1992).
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).
Y.-N. Sun, D. C. DuBois, R. R. Almon, and W. J. Jusko. 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. Pharmacokin. Biopharm. 26:289–317 (1998).
Y.-N. Sun, L. I. McKay, D. C. DuBois, R. R. Almon, and W. J. Jusko. Pharmacokinetic/pharmacodynamic models for corticosteroid receptor down-regulation and glutamine synthetase induction in rat skeletal muscle by a receptor/gene-mediated mechanism. J. Pharmacol. Exp. Ther. 288: 720–728 (1999).
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).
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. 49(Suppl.):2295s–2320s (1989).
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 (hsp90.hsp70.hsp56) 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).
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).
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).
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.
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).
D. Z. D'Argenio and A. Schumitzky. ADAPT II User's Guide: Pharmacokinetic/pharmacodynamic Systems Analysis Software, Biomedical Simulations Resource, Los Angeles, 1997.
O. M. Lowry, N. J. Rosebrough, A. L. Farr, and R. J. Randall. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 173:265–272 (1951).
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).
P. A. Krieg and D. A. Melton. In vitro RNA synthesis with SP6 RNA polymerase. Meth. Enzymol. 155:397–415 (1987).
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).
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. Molec. 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).
P-Pharm: Professional Desktop Data Modeling Software for Pharmacokinetics. Version 1.4, SIMED Scientific Software, France.
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).
A. J. Bailer. Testing for the equality of area under the curves when using destructive measurement techniques. J. Pharmacokin. Biopharm. 16:303–309 (1988).
J. R. Nedelman, E. Gibiansky, and D. T. W. Lau, Applying Bailer's method for AUC confidence intervals to sparse sampling. Pharm. Res. 12:124–128 (1995).
Y.-N. Sun and W. J. Jusko. Transmit compartments versus gamma distribution function to model signal transduction processes in pharmacodynamics. J. Pharm. Sci. 87:732–737 (1998).
L. I. McKay, D. C. DuBois, Y.-N. Sun, R. R. Almon, and W. J. Jusko. Corticosteroid effects in skeletal muscle: Gene induction/receptor autoregulation. Muscle Nerve 20:1318–1320 (1997).
J. Gabrielsson and D. L. Weiner. Parameter estimation. In Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts and Applications, 2nd ed., Swedish Pharmaceutical Press, 1997, pp. 31–57.
W. Mendenhall, D. D. Wackerly, and R. L. Scheaffer. Hypothesis testing. In Mathematical Statistics with Applications, PWS-KENT Publishing, 1990, pp. 427–491.
W. J. Jusko, H. C. Ko, and W. F. Ebling. Convergence of direct and indirect pharmacodynamic response models. J. Pharmacokin. Biopharm. 23:5–8 (1995).
D. B. Haughey and W. J. Jusko. Bioavailability and nonlinear disposition of methylprednisolone and methylprednisone in the rat. J. Pharm. Sci. 81:117–121 (1992).
S. J. Szefler, J. Q. Rose, E. F. Ellis, S. L. Spector, A. W. Green, and W. J. Jusko. The effect of troleandomycin on methylprednisolone elimination. J. Allergy Clin. Immunol. 66:447–451 (1980).
C. Monder and V. Lakshmi. Evidence for kinetically distinct forms of corticosteroid 11 β-dehydrogenase in rat liver microsomes. J. Steroid Biochem. 32:77–83 (1989).
H. Cheng and W. J. Jusko. Pharmacokinetics of reversible systems. Biopharm. Drug Dispos. 14:721–766 (1993).
A.-N. Kong and W. J. Jusko. Disposition of methylprednisolone and its sodium succinate prodrug in vivo and in perfused liver of rats: Nonlinear and sequential first-pass elimination. J. Pharm. Sci. 80:409–415 (1991).
M. Wakelkamp, G. Alvan, J. Gabrielsson, and G. Paintaud. Pharmacodynamic modeling of furosemide tolerance after multiple intravenous administration. Clin. Pharmacol. Ther. 60:75–88 (1996).
J. A. Bauer and H.-L. Fung. Pharmacodynamic models of nitroglycerin-induced hemodynamic tolerance in experimental heat failure. Pharm. Res. 11:816–823 (1994).
J. Shi, N. L. Benowitz, C. P. Denaro, and L. B. Sheiner. Pharmacokinetic-pharmacodynamic modeling of caffeine: tolerance to pressor effects. Clin. Pharmacol. Ther. 53:6–14 (1993).
G. Movin-Osswald and M. Hammerlund-Udenaes. Prolactin release after remoxipride by an integrated pharmacokinetic-pharmacodynamic model with intra-and interindividual aspects. J. Pharmacol. Exp. Ther. 274:921–927 (1995).
J. J. Lima, J. J. Krukemyer, and H. Boudoulas. Drug-or hormone-induced adaptation: Model of adrenergic hypersensitivity. J. Pharmacokin. Biopharm. 17:347–364 (1989).
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).
M. Gilli, J. J. Chiu, and M. J. Lenardo. NF-κB and Rel: Participants in a multiform transcriptional regulatory system. Int. Rev. Cytol. 143:1–62 (1993).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Sun, YN., DuBois, D.C., Almon, R.R. et al. Dose-Dependence and Repeated-Dose Studies for Receptor/Gene-Mediated Pharmacodynamics of Methylprednisolone on Glucocorticoid Receptor Down-Regulation and Tyrosine Aminotransferase Induction in Rat Liver. J Pharmacokinet Pharmacodyn 26, 619–648 (1998). https://doi.org/10.1023/A:1020746822634
Published:
Issue Date:
DOI: https://doi.org/10.1023/A:1020746822634