A Metabolic Study of Hydrocortisone in Rats

134

Zondek (1) as early as 1934 demonstrated that enzymes of the liver destroyed the biological activity of the estrogens. Since then both in tivo and in vitro studies have provided much evidence to show that the liver is the organ primarily responsible for the catabolism of the steroid hormones: estrogens, androgens, progesterone, and the corticosteroids (2). However, not until the development of improved methods for measurement of certain of the adrenocortical steroids and their metabolites, and the availability of labeled radioactive cortisol, corticosterone, and aldosterone has it been possible accurately to evaluate the influence of liver disease on the rate of degradation and synthesis of the steroids in man. The studies here reported are based on the use of certain of these newer techniques.On incubation with rat liver tissue, cortisol and cortisone are rapidly metabolized, but only very slowly with other tissues (3-5). Perfusion studies have demonstrated a very rapid metabolism of the steroids by the liver but not by other organs (6-8). Hechter, Frank, Caspi and Frank (9) found that the major portion of the cortisone and cortisol administered into the portal vein in dogs was not recovered as unaltered steroid from the hepatic venous blood. Bradlow, Dobriner and Gallagher (10) found that 70 per cent of a dose of tritium-labeled cortisone administered to mice was found in the liver within five minutes after intravenous administration. Administered cortisol also disappears rapidly from the circulation in rats (11), and this rapid metabolism can be prevented by hepatectomy but not by nephrectomy (12).The liver in man has a high capacity for metabolizing the circulating blood cortisol, as demonstrated by the fact that the level of 17-hydroxycorticosteroids in the hepatic vein blood is lower than the level in the arterial blood (13,14). Adrenocortical steroids administered intravenously

mentioning

confidence: 99%

Adrenocortical Steroid Metabolism and Adrenal Cortical Function in Liver Disease

Peterson¹

1960

134

“…In any case, the present data show that calculation of a single theoretical volume of distribution, v, is unwarranted since it is based on the assumption that the concentration of cortisol is the same throughout the entire volume of distribution as it is in the plasma. Since v proves to be larger than the total body volume both in these experiments and in those of others (6,10), the concentration of cortisol in sites of binding outside of the plasma appears to be much higher than in the plasma.…”

Section: Methodsmentioning

confidence: 88%

“…At a later Kelley (4) found that the half-life of 17-hydroxy- (6) found a half-life in 20 normal subjects of 114 ± 6.5 minutes, with a range of 90 to 130 minutes. This constant rate is due mainly to the activity of the liver, since Tomizawa, Narahara, Gibbons, and Williams (10) showed that hepatectomized rats did not metabolize cortisol, and Brown, Willardson, Samuels, and Tyler (3) found that in patients with liver disease the disappearance rate of 17-hydroxycorticosteroids was slowed proportional to the retention of bromosulfaphthalein. Peterson, Wyngaarden, Guerra, Brodie, and Bunim (6) also found increased half-lives in all their patients with liver disease.…”

Section: Methodsmentioning

confidence: 99%

“…The loss of steroid directly by renal excretion can be ignored since the quantities of unmetabolized cortisol entering the urine are negligible (5). The temporary rapid disappearance rates early in both experiments therefore presumably represent the rapid entry of cortisol into body compartments other than the plasma (i.e., a period of "equilibration" [10]). Since extracellular water contains no more cortisol than the plasma (11)(12)(13)(14)(15)(16), the steroid must enter the cells.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

The Effect of Intravenous Cortisol Injections on the Plasma Cortisol Concentration in Man 1

Scheuer¹,

Bondy²

1957

Previous workers have shown (1-7) that 17-hydroxycorticosteroids disappear rapidly from the plasma after cortisol (hydrocortisone) is injected intravenously. The disappearance rates have not, however, been studied in detail nor have analytical methods been used which would distinguish cortisol from its reduced derivatives. In the present experiments disappearance curves of cortisol have been determined, both after sudden massive injections, and during slow infusions at rates which permitted the establishment of equilibrium at physiological plasma cortisol concentrations. Steroid determinations have been performed by methods which separate cortisol from all other steroids known to be present in human plasma. MATERIALS AND METHODSAll subjects were healthy male medical students between the ages of 21 and 25. years, without evidence of serious disease or history of hepatic, renal or endocrinological abnormality. Studies were started between 8:30 and 9:30 a.m. The subjects were ambulatory but otherwise inactive. They were on normal diets throughout the experiment and all understood the nature of the procedure. Five subjects were used in each part and those who participated in Part I were not used in Part II.Heparinized blood samples were centrifuged immediately upon withdrawal and except in a few cases were extracted the same day. On occasion it was necessary to freeze the plasma for a few days prior to extraction. The plasma samples were analyzed by the method of Bondy, Abelson, Scheuer, Tseu, and Upton (8, 9), a brief description of which follows.Appropriate duplicate quantities of plasma were extracted with chloroform and the extracts chromatographed in the Bush toluene-75 per cent methanol paper chromatography system. Cortisol spots were eluted with ethyl alcohol and the quantity of steroid measured by potassium butoxide fluorometry (8). cortisol-4-C"4 were added to the original plasma sample and the radioactive recovery used to correct for losses during the procedure. The calculated standard deviation between duplicate samples with this method is +7 per cent, and recovery of added cortisol is 100 + 14 per cent. EXPERIMENTAL PROCEDUREPart I: A control blood specimen was drawn and then 100 mg. of cortisol (Upjohn) in 150 ml. of 6.7 per cent alcohol and 5 per cent glucose in water were injected over a 5-minute period through the same needle. Blood samples were taken at 15, 60, 150, 300, and 420 minutes from a vein in the opposite arm. In two subjects samples were taken every 15 minutes for the first hour and every 20 minutes for the second hour. The total amount of blood drawn was 320 ml.Part II: After an initial blood sample had been drawn, an infusion of cortisol in 500 ml. of 5 per cent glucose (Merck) was injected intravenously through a constant infusion pump at approximately 300 ,ug. per minute. Thereafter blood was withdrawn from the opposite arm at 60, 165, 180, 300, and 480 minutes. After withdrawal of the 180-minute sample the infusion was stopped and the solution run through the pump and needle into a 10...

“…The influence of such conversions on the over-all rate of disappearance of hydrocortisone from the body fluids may be masked by the strictly degradative processes. Both in vivo (8,11,12) and in vitro (13)(14)(15) experiments indicate that the liver plays a major role in the disappearance of hydrocortisone from the blood. That the chemical transformations in the liver are not essential for the biological activity of hydrocortisone is suggested by the fact that this steroid can exhibit its metabolic actions in the hepatectomized animal (16).…”

Section: Commentmentioning

confidence: 99%

Plasma and Urinary Steroids After Hydrocortisone Infusion 1

Sayers¹,

Glenn²,

Sydnor³

et al. 1955

The experiments presented in this report were designed to determine the rate of disappearance of intravenously administered hydrocortisone in patients with Addison's disease before routine steroid therapy had been initiated, during therapy and after therapy had been withdrawn. Tables I, II, and III. The fluorescent method is relatively specific for hydrocortisone (4) and, in the present study, where high levels of hydrocortisone were in-