Pharmacokinetics of prednisolone and endogenous hydrocortisone levels in cushingoid and non-cushingoid patients

Summary To establish if the appearance of cushingoid side effects in patients taking exogenous glucocorticoids is related to the disposition and metabolism of these steroids and endogenous hydrocortisone, 15 stable renal transplant patients and 12 patients treated with prednisone for oral mucocutaneous vesiculo-erosive diseases were investigated. All 27 patients were given their usual prednisone dose orally on one occasion, and 24 were given the same amount of prednisolone intravenously on another occasion. Following dosing, plasma samples were obtained for determination of the areas under the plasma concentration time curves of total prednisolone, prednisone and hydrocortisone by high performance liquid chromatography, and of unbound prednisolone by equilibrium dialysis. The bioavailability of prednisone, the interconversion of prednisone into prednisolone, the clearance of total and unbound prednisolone, the prednisolone binding capacity of albumin and transcortin, and the affinity of albumin for prednisolone did not differ between the 14 patients without cushingoid side effects and the 13 cushingoid patients. Compared to those who had cushingoid features, patients who developed no side effects had a higher affinity constant for prednisolone binding to transcortin – 2.04±0.27 × 10⁷ L/M vs. 1.34±0.16×10⁷ (X±SE;P&lt;0.05), more frequently exhibited peak hydrocortisone levels within the normal range (6/14 vs 1/13), more often had measurable (>10ng/ml) hydrocortisone in the plasma samples collected during the kinetic studies (123/291 vs 74/325;P<0.001) and had higher areas under the plasma concentration time curve of hydrocortisone (median, range), i.e. 8081 ng/ml · min (0–21 637 ng/ml · min) vs 386 ng/ml · min (0–16 329 ng/ml · min;P<0.005). The data suggest that endogenous hydrocortisone production is not as suppressed in patients with visible cushingoid signs as in noncushingoid patients, and that there is no significant difference in the pharmacokinetics of exogenous glucocorticoids between patients with and without cushingoid side effects.This work was presented in part to the American Society for Clinical Pharmacology and Therapeutics, 20th March, 1980, in San Francisco, and to the World Conference on Clinical Pharmacology and Therapeutics, 4th August, 1980, London