The Pharmacokinetics and Pharmacodynamics of Methylprednisolone in Chronic Renal Failure.
Methylprednisolone (MP) pharmacokinetics and its directly suppressive effects on cortisol secretion, circulating T-cells, and basophils in blood were compared in six chronic renal failure (CRF) subjects and six healthy controls after an IV administration of MP 0.6 mg kg(minus sign1) as the sodium succinate ester. The CRF subjects were studied between hemodialysis treatments. The total clearance of methylprednisolone sodium succinate (the prodrug) was reduced by 40% in CRF; however, the pharmacokinetics of methylprednisolone remained unchanged. Methylprednisolone clearance was approximately 280 ml h(minus sign1) kg(minus sign1) and volume of distribution was about 1.1 L kg(minus sign1). Physiological pharmacodynamic models were applied for the immediate effects of MP, based on the premise that receptor binding is followed by rapid suppression of the secretion of cortisol and recirculation of basophils, T-helper cells, and T-suppressor cells, which persist until inhibitory concentrations (IC(50)) of methylprednisolone disappear. The difference in IC(50) for each pharmacodynamic parameter was not statistically significant, suggesting no difference in the responsiveness of these factors to methylprednisolone in CRF. As the pharmacokinetics of other corticosteroids are altered in CRF, the lack of pharmacokinetic and pharmacodynamic changes of methylprednisolone may engender a therapeutic advantage for this corticosteroid in CRF.
Milad
Mark A.
MA
Department of Pharmaceutics, Pharmacy and Medicine, Schools of Pharmacy and Medicine, The State University of New York at Buffalo and Department of Pharmacy and Medicine, Buffalo General Hospital, Buffalo, USA.
Ludwig
Elizabeth A.
EA
Lew
Kim H.
KH
Kohli
Romesh K.
RK
Jusko
William J.
WJ