Evaluation of dose-related pharmacokinetics and pharmacodynamics of prednisolone in man

Abstract

The pharmacokinetics and pharmacodynamics of prednisolone were evaluated in normal male volunteers. Seven subjects completed 3 phases: 16.4- and 49.2-mg iv prednisolone, and a phase with no drug to assess baseline responses. Plasma concentrations of prednisolone and urine concentrations of prednisolone and 5 metabolites were assayed by HPLC. Protein binding of prednisolone was measured by ultrafiltration. The polyexponential disposition of free and total plasma prednisolone were evaluated and apparent parameters were compared between doses. Suppression of plasma cortisol and alterations in blood basophil and helper-T cell trafficking were used as pharmacodynamic indices. Pharmacodynamic models were used to relate total or free plasma prednisolone concentrations to each of these effects generating response parameters and IC50 (50% inhibitory) concentrations common to both doses. The pharmacokinetics of total drug were comparable to previous findings with CL and Vss increasing with dose. Free prednisolone exhibited slight capacity-limited elimination and distribution as CL and Vss decreased with the larger dose. Pharmacodynamic models jointly fitting all three phases characterized the suppression/trafficking phenomena equally well with use of total or free drug concentrations. In each case the models provided realistic values of parameters relating to steroid sensitivity--in particular IC50--and to the underlying physiology of the affected systems. This study comprehensively elucidates the complexities of prednisolone pharmacokinetics and demonstrates how plasma concentration--time profiles of total or free prednisolone can be utilized for evaluation of prednisolone pharmacodynamics.

Suppression of human monocyte tumour necrosisfactor-alpharelease by glucocorticoid therapy: relationshipto systemic monocytopaenia and cortisol suppression

“…Plasma cortisol concentrations recover abruptly after suppression, were very similar for orally-administered prednisolone and for prednisolone added after blood was collected. Again, this reflecting the pulsatile nature of secretion [11]. This would have occurred at some time between 24 and 48 h in these indicates that the actions of prednisolone are likely to be direct.…”

“…This may be insufficient for a clinicallyrelevant effect on TNF-a release. Furthermore, prednisolone concentrations decline rapidly after a conventional oral dose, [11,13]. There is no information on the duration of release with the glucocorticoid antagonist, mifepristone and by determining whether the relationship between prednisomonocyte/macrophage response after transient exposure to glucocorticoids and, therefore, no means to predict whether lone concentrations in the blood of the volunteers and TNF-a suppression could be reproduced by adding prednisoany effects of glucocorticoids in vivo would persist as the drug was eliminated.…”

“…Indeed, the concentrations measurable in blood during therapy with the glucocorticoid, arthritis, multiple sclerosis and other inflammatory diseases [1][2][3]. Glucocorticoids are effective anti-inflammatory and prednisolone, can reach the level which would be expected to suppress monokine production in vitro [11]. However, immunosuppressive agents, with actions on most cells involved in inflammatory or immune responses [4].…”

“…In vitro, whereas the free concentration of prednisolone would be expected to approximate the total concentration under glucocorticoids suppress release of TNF-a and a wide range of other monocyte/macrophage activities [5][6][7][8]. Glucoexperimental conditions, the free fraction of prednisolone in blood is concentration-dependent and may be only 5% of corticoids also provide relative protection from lethality in experimental endotoxaemia, suggesting capacity to suppress the total [11,12]. This may be insufficient for a clinicallyrelevant effect on TNF-a release.…”

Clinical Pharmacokinetics of Triple Immunosuppression Scheme in Kidney Transplant (Tacrolimus, Mycophenolate Mofetil and Corticosteroids)

“…The pharmacokinetics of prednisolone and prednisone are complicated by dose-dependency due to nonlinear protein binding (Wald et al, 1992). Protein binding of prednisolone decreases nonlinearly from 95% to 60-70%, while the concentration increases from 200 60-70%, while the concentration increases from 200 μg/L to 800 μg/L when protein binding of prednisolone reaches the stationary state (Rose et al, 1981).…”