Abstract
A two-compartment closed model was used to characterize the movement of basophils between blood and extravascular sites resulting from methylprednisolone (MP) exposure. This model is consistent with the view that corticosteroids cause a decrease in the recirculation of these cells from peripheral compartments. Methylprednisolone (Solu-Medrol) was given to healthy males at doses of 10, 25, and 40 mg. Blood samples were collected and assayed for MP by HPLC for pharmacokinetic analysis. Whole blood histamine, an index of circulating basophils, was assessed by RIA over 32 hr. Nonlinear least-squares analysis was carried out to solve for the model parameters reflecting cell movement between compartments and sensitivity (IC50)to the steriod. This model quantitates the fall and return pattern of biologic response to corticosteroids with a minimal number of parameters which jointly fit several dose/response curves and yields a mean IC50 value of 8.1 ng/ml similar to receptor binding of MP. Properties of the temporal and integrated response curve and model extrapolations over a wide dose range were explored with simulations. Because corticosteroids exert similar effects on other cells in blood, this model may be applicable to various regulatory and immunosuppressive effects.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
T. R. Cupps and A. S. Fauci. Corticosteroid-mediated immunoregulation in man.Immunol. Rev. 65:133–155 (1982).
P. M. Guyre, M. T. Girard, P. M. Morganelli, and P. D. Mangaliello. Glucocorticoid effects on the production and actions of immune cytokines.J. Steroid Biochem. 30:89–93 (1988).
A. P. Saavedra-Deigado, K. P. Mathews, P. M. Pan, D. R. Kay, and M. L. Muilenberg. Dose-response studies of the suppression of whole blood histamine and basophil counts by prednisone.J. Allergy Clin. Immunol 66:464–471 (1980).
R. P. Schleimer. The effects of glucocorticoids on mast cells and basophils. In R. P. Schleimer, H. N. Claman, and A. L. Oronsky (eds.),Anti-Inflammatory Steroid Action-Basic and Clinical Aspects, Academic Press, San Diego, CA, pp. 226–258.
E. H. Dunsky, B. Zweiman, E. Fischler, and D. A. Levy. Early effects of corticosteroids on basophils, leukocyte histamine, and tissue histamine.J. Allergy Clin. Immunol. 63:426–432 (1979).
E. J. Leonard and A. Skeel. Separation of human basophils into two fractions with different density and histamine content.J. Allergy Clin. Immunol. 76:556–562 (1985).
E. J. Leonard. Two populations of human blood basophils: Effect of prednisone on circulating numbers.J. Allergy Clin. Immunol. 79:775–780 (1987).
A.-N. Kong, E. A. Ludwig, R. L. Slaughter, P. M. DiStefano, J. DeMasi, E. Middleton Jr., and W. J. Jusko. Pharmacokinetics and pharmacodynamic modeling of direct suppression effects of methylprednisolone on serum cortisol and blood histamine in human subjects.Clin. Pharmacol. Ther. 46:616–628 (1989).
C. W. Parker, M. G. Huber, and M. L. Baumann. Alterations in cyclic AMP metabolism in human bronchial asthma. III. Leucocyte and lymphocyte responses to steroids.J. Clin. Invest. 52:1342–1348 (1973).
A. S. Fauci and D. C. Dale. The effect ofin vivo hydrocortisone on subpopulations of human lymphocytes.J. Clin. Invest. 53:240–246 (1974).
A. S. Fauci and D. C. Dale. The effect of hydrocortisone on the kinetics of normal human lymphocytes.Blood 46:235–243 (1975).
J. M. Engler, R. Y. Chestnut, G. C. Borst, and C. Eil. The effects of triacetyloleandomycin and oleandomycin phosphate on the glucocorticoid receptors in clutured skin fibroblasts.J. Allergy Clin. Immunol. 75:395–400 (1985).
P. Rohdewald, H. W. Mollman, and G. Hochhaus. Affinities of glucocorticoids for glucocorticoid receptors in the human lung.Agents Actions 17:290–291 (1989).
E. C. Butcher. Cellular and molecular mechanisms that direct leukocyte traffic.Am. J. Palhol. 136:3–11 (1990).
R. P. Schleimer. Effects of glucocorticosteroids on inflammatory cells relevant to their therapeutic applications in asthma.Am. Rev. Resp. Dis. 141:S59-S69 (1990).
B. Oosterhuis, I. J. M. TenBerge, P. T. A. Schellekens, R. P. Koopmans, and C. J. van Boxtel. Prednisolone concentration-effect relations in humans and the influence of plasma hydrocortisone.J. Pharmacol. Exp. Ther. 239:919–926 (1986).
E. Bloemena, S. Weinreich, and P. T. A. Schellekens. The influence of prednisolone on the recirculation of peripheral blood lymphocytesin vivo.Clin. Exp. Immunol. 80:460–466 (1990).
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).
L. K. Johnson, J. P. Longnecker, J. D. Baxter, M. F. Dallman, E. P. Widmaier, and N. L. Eberhardt. Glucocorticoid action: A mechanism involving nuclear and non-nuclear pathways.Br. J. Dermatol. 107(Suppl. 23):6–23 (1982).
G. P. Lewis, W. J. Jusko, C. W. Burke, L. Graves, and the Boston Collaborative Drug Surveillance Program. Prednisone side effects and serum protein levels.Lancet 2:778–781 (1971).
W. G. Reiss, R. L. Slaughter, E. A. Ludwig, E. Middleton Jr., and W. J. Jusko. Steroid dose sparing: Pharmacodynamic responses to single versus divided doses of methylprednisolone in man.J. Allergy Clin. Immunol. 85:1058–1066 (1990).
H. Derendorf, H. Möllmann, M. Krieg, S. Tunn, C. Möllmann, M. Krieg, S. Tunn, J. Barth, and H. J. Röthig. Pharmacodynamics of methylprednisolone phosphate after single intravenous administration to healthy volunteers.Pharm. Res. 8:263–268 (1991).
T. E. Dunn, E. A. Ludwig, R. L. Slaughter, D. S. Camara, and W. J. Jusko. Pharmacokinetics and pharmacodynamics of methylprednisolone in obese and non-obese men.Clin. Pharmacol. Ther. 50:536–549 (1991).
Author information
Authors and Affiliations
Additional information
This work was supported in part by Grants GM 24211 and 150-1885-0 from the National Institute of General Medical Sciences, NIH.
Rights and permissions
About this article
Cite this article
Wald, J.A., Salazar, D.E., Cheng, H. et al. Two-compartment basophil cell trafficking model for methylprednisolone pharmacodynamics. Journal of Pharmacokinetics and Biopharmaceutics 19, 521–536 (1991). https://doi.org/10.1007/BF01062961
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF01062961