Cortisol pharmacodynamics after methylprednisolone administration in young and elderly males

Abstract

Glucocorticoids are commonly prescribed in the elderly on an empiric basis with little consideration for the age-related alteration sin pharmacologic response. The objectives of this study were to compare the effect of methylprednisolone on cortisol patterns in elderly and young healthy men, to define the relationship between pharmacokinetic parameters of methylprednisolone and pharmacodynamics of cortisol in the elderly and young men. Seven healthy, elderly males (69-82 years old) and five healthy, young males (24-37 years old) participated in a 24-hour pharmacodynamic trial with randomized assignment to a control period (Phase I) and a methylprednisolone period (Phase II). Serial blood samples were obtained throughout both study periods. Cortisol measurements included the total area under the concentration-time curve (AUC), return AUC, and suppression ratio. During Phase I, a circadian pattern was noted in both groups. After exposure to methylprednisolone (Phase II), a linear decline in serum concentrations of cortisol was observed in both groups. The return AUC of cortisol (425 ± 357 ng · hr/mL [elderly] versus 854 ± 216 ng · hr/mL [young]) and the total AUC 764 ± 340 ng · hr/mL [elderly] versus 1,230 ± 258 ng · hr/mL [young]) were significantly lower in the older men. In addition, a significant decline in total AUC and nadir concentration of cortisol from Phase I to Phase II was noted within both groups. The suppression ratio was significantly greater in the elderly men (mean, 0.38 versus 0.58 in young), which indicates a greater degree of adrenal suppression after administration of methylprednisolone. Exposure to methylprednisolone, as measured by AUC, was 554 ± 215 ng · hr/kg (elderly) and 389 ± 102 ng · hr/kg (young). The greater exposure to methylprednisolone noted in the elderly yielded significant combined correlations for both groups with AUC, return AUC, and suppression ratio of cortisol. A more significant response of cortisol to the exogenous glucocorticoid was apparent in the elderly men. In addition, a slower clearance of methylprednisolone was noted in the elderly group compared with their young counterparts. The effect of reduced clearance of methylprednisolone on the suppression ratio indicates the interrelationship between the disposition of a single dose of an exogenous glucocorticoid and response patterns of cortisol.