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<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.
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Brooks SM, Werk EE, Ackerman SJ, Sullivan I, Thrasher K (1972) Adverse effects of phenobarbital on corticosteroid metabolism in patients with bronchial asthma. N Engl J Med 286: 1125–1128
McEnery PH, Stempel DA (1976) Commentary: Anticonvulsant therapy and renal allograft survival. J Pediatr 88: 138–139
Kozower M, Veatch L, Kaplan MM (1974) Decreased clearance of prednisolone, a factor in the development of corticosteroid side effects. J Clin Endocrinol Metab 38:407–412
Gambertoglio J, Vincenti F, Feduska N, Birnbaum J, Salvatierra O, Amend W (1980) Prednisolone disposition in cushingoid and noncushingoid kidney transplant patients. J Clin Endocrinol Metab 51: 561–565
Rose JQ, Yurchak AM, Jusko WJ (1979) The apparent non-linear pharmacokinetics of prednisone and prednisolone: The role of protein binding. APhA Acad Pharm Sci Abstracts 9: 82
Gugler R, Shoeman DW, Huffman DH, Cohlmia JB, Azarnoff DL (1975) Pharmacokinetics of drugs in patients with the nephrotic syndrome. J Clin Invest 55: 1182–1189
Lewis GP, Jusko WJ (1971) Prednisone side-effects and serum-protein levels. Lancet 2: 778–781
Slaunwhite WR, Lockie GN, Back N, Sandberg AA (1962) Inactivity in vivo of transcortin-bound cortisol. Science 135: 1062–1063
Moel DI, Kwun YA (1978) Adrenal function in steroid treated minimal change nephrotic syndrome. Kidney Int 14: 656
Leisti S, Koskimies O, Rapola J, Hallman N, Perheentupa J, Vilska J (1977) Association of postmedication hypocortisolism with early first relapse of idiopathic nephrotic syndrome. Lancet 2: 795–796
Frey FJ, Frey BM, Benet LZ (1980) Steroids. In: Marton LJ, Kabra PM (eds) Liquid chromatography in clinical analysis. Humana Press
Frey FJ, Frey BM, Benet LZ (1979) Liquid chromatographic measurement of endogenous and exogenous glucocorticoids in plasma. Clin Chem 25: 1944–1948
Frey FJ, Frey BM, Greither A, Benet LZ (1980) Prednisolone clearance at steady-state in dogs. J Pharmacol Exp Ther 215: 287–291
Behm HL, Wagner JG (1979) Errors in interpretation of data from equilibrium dialysis protein binding experiments. Res Commun Chem Pathol Pharmacol 26: 145–160
Rocci ML, Baliah TB, Jusko WJ (1980) Protein binding of prednisolone in normal and nephrotic serum. APhA Acad Pharm Sci Abstracts 10: 83
Muldoon TG, Westphal V (1967) Steroid-protein interactions XV, isolation and characterization of corticosteroid binding globulin from human plasma. J Biol Chem 242: 5636–5643
Holford NHG (1979) Multifun. In: Perry HM, Wood JJ (eds) Public procedures notebook. Bolt, Beranek and Newman, Inc., Cambridge, Mass.
Mancini G, Carbonara A, Heremans J (1965) Immunochemical quantitation of antigens by single radial immunodiffusion. Immunochemistry 2: 235–254
Putnam FW (1975) The plasma proteins; structure, function and genetic control. Academic Press, New York
Gibaldi M, Perrier D (1975) Pharmacokinetics. Marcel Dekker, New York, pp 293–296
Benet LZ, Galeazzi RL (1979) Noncompartmental determination of the steady-state volume of distribution. J Pharm Sci 68: 1071–1074
Zar JH (1974) Biostatistical analysis. Prentice Hall, Englewood Cliffs, NJ
Normal reference laboratory values (1980) N Engl J Med 302: 37–48
Schalm SW, Summerskill WHJ, Go VLG (1977) Prednisone for chronic active liver disease: pharmacokinetics, including conversion to prednisolone. Gastroenterology 72: 910–913
Hulme, B, James VHT, Rault R (1975) Absorption of enteric and non-enteric coated prednisolone tablets. Br J Clin Pharmacol 2: 317–320
Petereit LB, Meikle AW (1977) Effectiveness of prednisolone during phenytoin therapy. Clin Pharmacol Ther 22: 912–916
Rose JQ, Yurchak AM, Jusko WJ (1978) Bioavailability of two 50mg prednisone formulations in man. Abstract APhA Acad Pharm Sci 8:138
Uribe M, Schalm SW, Summerskill WHJ, Go VLW (1978) Oral prednisone for chronic active liver disease: dose responses and bioavailability studies. Gut 19: 1131–1135
DeMoor P, Steeno O, Brosens I, Hendrikx A (1966) Data on transcortin activity in human plasma as studied by gel filtration. J Clin Endocrinol 26: 71–78
Westphal U (1971) Steroid protein interactions. Springer, Berlin Heidelberg New York, p 225
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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
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Frey, F.J., Amend, W.J.C., Lozada, F. et al. Pharmacokinetics of prednisolone and endogenous hydrocortisone levels in cushingoid and non-cushingoid patients. Eur J Clin Pharmacol 21, 235–242 (1981). https://doi.org/10.1007/BF00627926
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DOI: https://doi.org/10.1007/BF00627926