The Physiological Disposition and Metabolic Fate of Cortisone in Man
Authors: Ralph E. Peterson, Charles E. Pierce, James B. Wyngaarden, Joseph J. Bunim, Bernard B. Brodie
Journal: Journal of Clinical Investigation (1957)

In an earlier paper we described studies on the physiological disposition and metabolic fate of hy- drocortisone in man (1).This paper describes similar studies on cortisone.Although contribut- ing very little to the body pool of adrenal corti- cal steroids, cortisone has been used extensively as a therapeutic agent, and it was therefore of in- terest to compare its metabolism with that of hy- drocortisone.Large doses of cortisone and hy- drocortisone were administered intravenously and rates of disappearance from the plasma determined in normal subjects and in patients with liver dis- ease, myxedema, thyrotoxicosis, and rheumatoid arthritis.Trace quantities of cortisone-4-C" and hydrocortisone-4-C" were employed in certain studies.From these studies, information was ob- tained regarding rate of metabolic transformation, rate of absorption, rates and routes of excretion of cortisone and its metabolites, and, to some ex- tent, the identity and amount of these metabolites.Information was also obtained on the in vivo con- version of cortisone to hydrocortisone. MATERIALS AND METHODSAdministration of steroid.The steroids were dissolved in 25 ml.ethanol and added to 500 ml. of sterile five per cent dextrose in water.This solution was administered intravenously over a period of 10 to 20 minutes.For oral or intramuscular administration the steroids were suspended in saline.Cortisone-4-C" was administered intravenously in trace quantities in a small volume of five per cent ethanol in water over a period of 3 to 5 minutes, or mixed with carrier cortisone and given in 500 ml. of three per cent ethanol in five per cent dextrose in sterile distilled water.Following the administration of the steroids, blood samples were drawn in heparinized syringes every 20 or 30 minutes for 2 hours-or more.Urine samples were collected and preserved by freezing.Methods of assay.The extraction procedures for the steroids in plasma and urine were the same as those de- 1Present address: Department of Medicine, Duke Uni- versity, Durham, North Carolina.scribed previously (1).Cortisone and certain of its metabolites in plasma were determined by a modification (2) of the original phenylhydrazine procedure of Silber and Porter (3).Specificity of this method of assay for plasma hydrocortisone after administration of hydro- cortisone was shown to be high, as tested by counter- current distribution and isotope dilution techniques.Us- ing these same techniques, it was found that the Silber- Porter method was much less satisfactory for the specific measurement of cortisone after the administration of cortisone.Counter-current distribution.Plasma drawn 60 min- utes after a 20-minute intravenous infusion of 200 mg. of cortisone was extracted with dichloromethane.A trace quantity of cortisone-4-C' was added to the dichloro- methane extract.The extract was evaporated to dryness, and the apparent cortisone subjected to a 16-trans- fer counter-current distribution.The solvents used were one volume of water as the upper phase and one volume of a mixture containing four parts carbon tetrachloride and one part dichloromethane as the lower phase.This system gave a partition coefficient of 1.5 for cortisone.After distribution, aliquots of both phases were assayed by the phenylhydrazine reaction, and for carbons4.Fig- ure 1 shows the distribution of the phenylhydrazine react- ing material in plasma, and the cortisone-4-C.The data indicate that more than one-half of the dichloro-