Prednisolone and prednisone are two widely used corticosteroids for various inflammatory and immune diseases. Prednisolone is the active form of prednisone in vivo. Total prednisolone in plasma exhibits nonlinear pharmacokinetics mainly due to its nonlinear protein binding. Other factors such as reversible metabolism (or interconversion between prednisolone and prednisone), competitive protein binding from endogenous cortisol, cortisol circadian rhythm, and prednisolone mediated cortisol suppression complicate prednisolone pharmacokinetics. This study was aimed to develop a new approach to describe the nonlinear pharmacokinetics of total prednisolone and predict total prednisolone concentrations in plasma. Based on literature datasets, a linear two-compartment pharmacokinetic model was developed to adequately describe the reversible metabolism between free prednisone and prednisolone. Cortisol and prednisolone protein binding were described via the sum of a Langmuir and linear type binding. The endogenous cortisol circadian rhythm and cortisol suppression during prednisone or prednisolone exposure were described with a previously reported linear release rate pharmacokinetic/pharmacodynamic (PK/PD) model. By combining the pharmacokinetic models for free prednisone and prednisolone, the linear release rate model for cortisol suppression, and competitive protein binding between cortisol and prednisolone, we were able to predict total prednisolone concentrations in plasma. The predicted total prednisolone concentrations in plasma were in good agreement with the literature reported data. Thus, this PK/PD approach shows that the combination of nonlinear protein binding, cortisol circadian rhythm, and cortisol suppression could account for the nonlinearity of total prednisolone. In addition, it also allows a valid prediction of total prednisolone in plasma after either prednisone or prednisolone administration.
Similar content being viewed by others
References
Pickup M.E. (1979). Clinical pharmacokinetics of prednisone and prednisolone. Clin. Pharmacokinet. 4:111–128
Boudinot F.D., Jusko W.J. (1986). Dose-dependent pharmacokinetics of prednisolone in normal and adrenalectomized rats. J Pharmacokinet. Biopharm. 14:453–467
Frey F.J., Frey B.M., Greither A., Benet L.Z. (1980). Prednisolone clearance at steady state in dogs. J. Pharmacol. Exp. Ther. 215:287–291
Huang M.L., Jusko W.J. (1990). Nonlinear pharmacokinetics and interconversion of prednisolone and prednisone in rats. J Pharmacokinet. Biopharm. 18:401–421
Pickup M.E., Lowe J.R., Leatham P.A., Rhind V.M., Wright V., Downie W.W. (1977). Dose dependent pharmacokinetics of prednisolone. Eur. J. Clin. Pharmacol. 12:213–219
Rose J.Q., Yurchak A.M., Jusko W.J. (1981). Dose dependent pharmacokinetics of prednisone and prednisolone in man. J. Pharmacokinet. Biopharm. 9:389–417
Wald J.A., Law R.M., Ludwig E.A., Sloan R.R., Middleton E. Jr., Jusko W.J. (1992). Evaluation of dose-related pharmacokinetics and pharmacodynamics of prednisolone in man. J. Pharmacokinet. Biopharm. 20:567–589
Ferry J.J., Wagner J.G. (1987). The nonlinear pharmacokinetics of prednisone and prednisolone. II. Plasma protein binding of prednisone and prednisolone in rabbit and human plasma. Biopharm. Drug Dispos. 8:261–272
Jusko W.J., Rose J.Q. (1980). Monitoring prednisone and prednisolone. Ther. Drug Monit. 2:169–176
Rocci M.L. Jr., D’Ambrosio R., Johnson N.F., Jusko W.J. (1982). Prednisolone binding to albumin and transcortin in the presence of cortisol. Biochem. Pharmacol. 31:289–292
Legler U.F., Benet L.Z. (1986). The effect of prednisone and hydrocortisone on the plasma protein binding of prednisolone in man. Eur. J. Clin. Pharmacol. 30:51–55
Rohatagi S., Hochhaus G., Mollmann H., Barth J., Derendorf H. (1995). Pharmacokinetic interaction between endogenous cortisol and exogenous corticosteroids. Pharmazie 50:610–613
Koopmans R.P., Braat M.C., Oosterhuis B., van Boxtel C.J. (1992). Time-dependent effects of dexamethasone administration on the suppression of plasma hydrocortisone, assessed with a pharmacokinetic model. J. Pharmacol. Exp. Ther. 262:503–508
Rohatagi S., Bye A., Mackie A.E., Derendorf H. (1996). Mathematical modeling of cortisol circadian rhythm and cortisol suppression. Eur. J. Pharmaceut. Sci. 4:341–350
Chakraborty A., Krzyzanski W., Jusko W.J. (1999). Mathematical modeling of circadian cortisol concentrations using indirect response models: comparison of several methods. J. Pharmacokinet. Biopharm. 27:23–43
Ferry J.J., Horvath A.M., Bekersky I., Heath E.C., Ryan C.F., Colburn W.A. (1988). Relative and absolute bioavailability of prednisone and prednisolone after separate oral and intravenous doses. J. Clin. Pharmacol. 28:81–87
Chakraborty A., Blum R.A., Mis S.M., Cutler D.L., Jusko W.J. (1999). Pharmacokinetic and adrenal interactions of IL-10 and prednisone in healthy volunteers. J. Clin. Pharmacol. 39:624–635
Meno-Tetang G.M., Blum R.A., Schwartz K.E., Jusko W.J. (2001). Effects of oral prasterone (dehydroepiandrosterone) on single-dose pharmacokinetics of oral prednisone and cortisol suppression in normal women. J. Clin. Pharmacol. 41:1195–1205
D. Z. D’Argenio and A. Schumitzky. ADAPT II User’s Guide: Pharmacokinetic/pharmacodynamic Systems Analysis Software, 1997.
Gustavson L.E., Benet L.Z. (1985). The macromolecular binding of prednisone in plasma of healthy volunteers including pregnant women and oral contraceptive users. J. Pharmacokinet. Biopharm. 13:561–569
Derendorf H., Mollmann H., Barth J., Mollmann C., Tunn S., Krieg M. (1991). Pharmacokinetics and oral bioavailability of hydrocortisone. J. Clin. Pharmacol. 31:473–476
Boudinot F.D., Jusko W.J. (1984). Plasma protein binding interaction of prednisone and prednisolone. J. Steroid Biochem. 21:337–339
W. E. Evans, J. J. Schentag, and W. J. Jusko. Applied Pharmacokinetics : Principles of Therapeutic Drug Monitoring. Lippincott Williams & Wilkins, Vancouver, 1992, p. Ch27.
Baxter J.D., Rousseau G.G. (1979), Glucocorticoid Hormone Action. Monographs on Endocrinology, Vol. 12. Springer-Verlag, Berlin, New York, pp. 26–27
Garg V., Jusko W.J. (1994). Bioavailability and reversible metabolism of prednisone and prednisolone in man. Biopharm Drug Dispos. 15:163–172
Schwartz J.I., Mukhopadhyay S., Porras A.G., Viswanathan-Aiyer K.J., Adcock S., Ebel D.L., Gertz B.J. (2003). Effect of rofecoxib on prednisolone and prednisone pharmacokinetics in healthy subjects. J. Clin. Pharmacol. 43:187–192
Frey B.M., Frey F.J. (1990). Clinical pharmacokinetics of prednisone and prednisolone. Clin. Pharmacokinet. 19:126–146
Gambertoglio J.G., Amend W.J. Jr., Benet L.Z. (1980). Pharmacokinetics and bioavailability of prednisone and prednisolone in healthy volunteers and patients: a review. J. Pharmacokinet. Biopharm. 8:1–52
Frey F.J., Ruegsegger M.K., Frey B.M. (1986). The dose-dependent systemic availability of prednisone: one reason for the reduced biological effect of alternate-day prednisone. Br. J. Clin. Pharmacol. 21:183–189
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Xu, J., Winkler, J. & Derendorf, H. A Pharmacokinetic/Pharmacodynamic Approach to Predict Total Prednisolone Concentrations in Human Plasma. J Pharmacokinet Pharmacodyn 34, 355–372 (2007). https://doi.org/10.1007/s10928-007-9050-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10928-007-9050-8