Pharmacokinetics and pharmacodynamic modeling of direct suppression effects of methylprednisolone on serum cortisol and blood histamine in human subjects

Abstract

Pharmacodynamic models for "directly suppressive" effects of methylprednisolone are based on the premise that receptor interactions of steroids are followed by immediate suppression of either the circadian secretion of cortisol or the constant rate recirculation of histamine-containing basophils that persists until inhibitory concentrations of methylprednisolone disappear. Methylprednisolone doses of 0, 10, 20, and 40 mg were given as the 21-succinate sodium salt in a balanced crossover study to six normal men. Plasma steroid concentrations and blood histamine were measured simultaneously. Both forms of methylnisolone exhibited linear kinetic parameters. One dynamic model quantitates the baseline circadian pattern and the decline and return of cortisol with similar parameter estimates for all three dose levels. A similar model describes the monoexponential decline and the log-linear return to steady-state baseline of blood histamine. Similar inhibitory concentration values for both effects approximated the equilibrium dissociation constant of in vitro steroid receptor binding. The new models are more physiologically appropriate for these steroid effects than three other models that are commonly employed in pharmacodynamics. Steroid effects generally appear to be receptor mediated with either nongene immediate responses or gene-mediated delayed effects. These models allow quantitation of the rapid effects of steroids with simple equations and common fitted parameters for all steroid dose levels.The diverse immunosuppressive and the antiinflammatory effects of glucocorticoids in human beings complicate the development of realistic and comprehensive kinetic and dynamic models for this class of agents. This is partly because of the complex mode of action of corticosteroids, which involves receptor binding and the formation of second messengers and proteins (which is mediated by deoxyribonucleic acid [DNA]). Such responses are typically characterized by a slow and delayed induction period. This receptorReprint requests: William J. Jusko, PhD, 565 Hochstetter Hall, School of Pharmacy, State University of New York at Buffalo, Buffalo, NY 14260. Presented in part at the Third Annual Meeting of American Association of Pharmaceutical Scientists (AAPS), Orlando, Florida, Oct. 30 to Nov. 3, 1988. NIH Public Access Author ManuscriptClin Pharmacol Ther. Author manuscript; available in PMC 2014 October 23. Published in final edited form as:Clin Pharmacol Ther. 1989 December ; 46(6): 616-628. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript gene mode of action has been successfully modeled for prednisolone effects in rats. 1,2 In human beings, pharmacodynamic modeling of glucocorticoid responses has focused on Sheiner's model 3 of linkage of a hypothetical "effect compartment" to the plasma concentration. This approach has been used to characterize the fall and return of OKT3-and OKT4-positive lymphocytes in peripheral blood after single oral doses of prednisolone. 4 A threshold concentratio...

Gender-based effects on methylprednisolone pharmacokinetics and pharmacodynamics

“…Recently pharmacodynamic models that describe the direct suppressive effects of corticosteroids have been used to characterize the response patterns of plasma cortisol concentrations, blood basophil counts (measured as whole blood histamine), and helper T lymphocyte counts after administration of methylprednisolone to young healthy male subjects. [15][16][17] These models are applied in this study to jointly examine the pharmacokinetics and pharmacodynamics of methylprednisolone in relation to gender. …”

Pharmacokinetics and pharmacodynamics of methylprednisolone when administered at 8 AM versus 4 PM

“…Several studies have shown that 10 to 40 mg methylprednisolone administered in the morning produce appreciable suppression of cortisol concentrations. 19,36,37 We found a similar degree of net suppression of cortisol concentrations in both phases; however, the normal circadian rhythm was significantly altered by the 4 PM dose. This dose produces nadir cortisol concentrations around the time that cortisol concentrations are normally increasing, thus perturbing the normal circadian cycle.…”

“…Pharmacodynamic models that describe these direct suppressive effects are shown with the experimental data. 19,30 These models account for both the pharmacokinetics of the administered corticosteroid along with the suppression and return to baseline of the measured pharmacodynamic parameter.…”

“…Pharmacodynamic models that describe these direct suppressive effects are shown with the experimental data. 19,30 These models account for both the pharmacokinetics of the administered corticosteroid along with the suppression and return to baseline of the measured pharmacodynamic parameter.After intravenous administration of methylprednisolone, whole blood histamine (H) concentrations decline linearly with a first-order rate constant (k h ). Corticosteroids arc postulated to inhibit the zero-order rate of return of basophils from the extra vascular compartment to the blood , whereas the movement of basophils from the blood is unaffected.…”

“…Pharmacodynamic models developed in this laboratory for these effects were used. 19,20 Methylprednisolone, rather than prednisolone, was chosen for study because its kinetics is linear at low doses and thus less complicated to study. 21 …”