Metabolism and Kinetics of Adrenocortical Steroids. -A Consideration on Corticosteroid Therapy-
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1 Metabolism and Kinetics of Adrenocortical Steroids -A Consideration on Corticosteroid Therapy- Yoshitaka Araki First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo I. Introduction Manyfundamental studies have been made on the mechanismof physiological and pharmacological action of adrenocortical hormones but its clinical application seems to be based primarily on experience regarding its therapeutic effect and side effects. It is true that the potency of corticosteroids is dependent on the reactivity of peripheral target tissue, as with other pharmaceutics, but it seems to be determined by the so-called intensity and duration factors. The present work was undertaken in order to re-examine corticosteroid therapy from the metabolism and kinetics of adrenocortical steroids and to obtain a theoretical basis for administration of the corticosteroid. Subjects chosen for this study were humanbeings, and observations were made on both normal and diseased subjects. II. Kinetics of Endogenous Corticosteroid Corticosteroid is often used at the time of the so-called stress, such as infectious diseases and feverish state, in order to effect systemic improvement and antifebrile effect. In majority of such cases, it is often obscure whether the corticosteroid administration had been made from the point of hormonereplacement therapy or for pharmacological therapy. As long as the adrenocortical hormones have the nature of adaptive hormone, it is important in discussing the virtues of this therapy to know whether the hormone had been used for replacement therapy to supply the relatively insufficient amount of secretion for biological requirement at the time of the attack of infectious diseases or whether such administration had been made
2 440 Araki Jap. J. Med. 1963' as a pharmacological therapy to expect antiphlogistic action. In recent years, it has become possible to obtain labeled corticosteroids of high specific activity and to study kinetics of human corticosteroids by the progress of measuring apparatus, which added new observations. In order to find the significance of corticosteroid therapy at the time of infection and fever, examinations were made on acute and chronic stress states by the use of a tracer dose of cortisol-4-14c, by clarifying the amount of secretion, turnover rate, and body distribution of endogenous cortisol. (1) Kinetics Model of Cortisol-4-j4C in Human Body: Blood was drawn serially at various times after intravenous injection of ljuc of cortisol-4-14c (specific activity, 25//c/mg.) and urine was collected during 24 hours after the injection. Radioactivity of each fraction of blood, and the free fraction, glucuronide fraction, and the fraction extracted at ph 1 of the 24-hour urine was measured with a liquid scintillation counter. Radioactivity of the free plasma fraction was plotted on a semi-logarithmic axis and the value was obtained as a curve representing the sum of two exponential functions. Consequently, pool of free-type cortisol in a human body is present in plural numbers and it was assumed that a two-compartment model would be more appropriate as the kinetics model of cortisol, as was assumed by Laumas and Tait for aldosterone. Simultaneous differential equation to describe the transfer of radioactivity Fig. 1.
3 Vol. 2, No. 3 METABOLISM AND KINETICS OF STEROIDS 441 is shown in Fig. 1 and it becomes possible to calculate from it the size of each pool, transfer between compartments during unit time,.and the amount secreted in unit time for cortisol. (2) Normal Person: Biological half-time of the disappearance of radioactivity in the free fraction of plasma cortisol for a normal person was approximately 80 minutes and the secretion rate was about 20mg./day. The size of pool in thiscase was 0.45mg. forthe 1st pool and 0.9mg. for the 2nd pool, and these values were approximately commonto all normal cases examined. Apparent distribution volume of cortisol in the 1st pool was 4-5L. and these data suggest that cortisol can easily disperse and distribute into the extracellular phase from blood vessel. It is not clear whatthe 2nd pool signifies but it is certain that it is present in the form of a concentrated state with the cells of systemic tissue, at least when there is increased secretion, as will be stated below. This is also endorsed bythefact that, if the concentration inside that pool is assumed to be equal to that in the plasma, the apparent total distribution volume would reach several dozen liters. (3) Maximal Stimulation with ACTH: Intramuscular injection of ACTH to a normal person, 40 units on the first day and 80 units on the second day, and examination of the kinetics of cortisol when adrenal cortex is known to be in a maximal stimulated state, showed that both the secretion rate and the size of each pool were markedly increased. (4) In the State of Acute Stress: Secretion rate 4 hours after gastrectomy in a patient of carcinoma of the stomach was 9.2mg./hour, which would be over 221 mg. per day. The poolswere markedly increased, as inthe case of ACTH stimulation, the 2nd pool was approximately double the 1st pool, and transfer rate during unit time between the pools also in- 'Creased. When 50mg. of etiocholanolone, one of pyrogenic steroids, was injected intramuscularly to a normal person and a high fever of around 40 C was produced during a few hours, as a state of acute stress, secretion rate was only 2.0mg./hr., or around 50mg. per day, but the half-time of disappearance from blood markedly extended to
4 442 Araki Jap. J. Med minutes. This may be due partly to the increase in distribution volume but mainly indicates that there is retardation of metabolism of cortisol in the liver, especially that of conjugation. These facts indicate that the control of corticosteroid supply, required by the body at the time of stress, is not only made by secretion from the adrenal cortex but metabolism of corticosteroid in the liver also takes part to increase the utilization rate of the secreted free-type cortisol. In other words, this is an adaptive or compensative mechanism. (5) In the State of Chronic Stress: The same examinations were made with patients of infectious disease, having fever over a long period. Its result showed that while daily secretion rate of cortisol was in a normal range, the half-time of its disappearance from blood was fairly extended. Entirely the same tendency was observed in untreated, rheumatic fever patient with continued fever. In both of these cases, both pools were increased, though slightly, and the 2nd pool was larger than the 1st in both cases. Slight increase of the pools without increase in secretion rate, probably indicate decreased turnover rate of cortisol and this is another evidence that the insufficient secretion of the hormone required by the body at the time of chronic stress, is partly supplemented by the change in turnover rate in the liver. However, with absence of increase in secretion rate and extension of the halftime of plasma removal, as observed in a case of tuberculous peritonitis, it sometimes happens that the 2nd pool is smaller than the 1st pool. In such a case, increased hormonal secretion would naturally be required at the time of stress like fever but even the compensatory decrease of turnover rate in the liver is assumed to be incapable of maintaining a sufficient supply of the hormone to the tissue. Summary and Discussion The foregoing experimental facts may be summarized as follows : At the time of acute stress, as in the case of ACTHadministration, there are (A) marked increase of cortisol secretion from the adrenal cortex, (B) increase of the pool, and (C) slight decrease of turnover rate.
5 Vol. 2, No. 3 METABOLISM AND KINETICS OF STEROIDS 443 At the time of repeated or continuous attack resulting in chronic stress, there are (a) insufficiency or lack of cortisol secretion response, (b) very slight increase of cortisol pool in the body, and (c) a marked decrease of turnover rate of cortisol in the liver. Consequently, it is clear that there is a definite unbalance between the hormone demand in the tissue at the time of stress and the amount of its secretion from the adrenal cortex. In such a case, supply of adrenocortical hormone from outside is considered to be necessary. Administration of adrenocortical hormones at the time of infection or continued fever has the significance of replacement therapy, anticipating true systemic hormone action, besides pharmacological action against local process to cause chronic stress. III. Metabolism and Kinetics of Synthetic Corticosteroids Metabolism of synthetic corticosteroids, which have different structure from that of cortisol, which might be of clinical interest will be stated. When such steroids, which are actually foreign to a living body, enter the body, there may be some difference in their metabolism from that of cortisol and this point was examined. (1) Metabolic Characteristics of Synthetic Corticosteroids : Cortisol, prednisolone, and dexamethasonewere given to normal persons and their disappearance from blood and urinary excretion were examined. Rate of disappearance from blood decreased in the order of cortisol, prednisolone, and dexamethasone. The rate of urinary excretion of the synthetic derivatives in the free form was greater than that of cortisol. Examination was also made with labeled steroids by intravenous injection of 20mg. of cortisol-4-14c, prednisolone-3h, or triamcinolone- 3H with a carrier respectively (Fig. 2). The half-time of the second slope of the curve for disappearance of their radioactivity was the shortest in cortisol, followed by prednisolone, and the longest in triamcinolone. The size of apparent distribution volume, obtained by extrapolation of the second slope of this curve, decreased in the order of triamcinolone, prednisolone, and cortisol. Radioactivity of the conjugate fraction of triamcinolone in blood was markedly small.
6 444 Araki Jap. J. Med Fig. 2. On the other hand, excretion of radioactivity into the free fraction in urine was far greater in the synthetic derivatives than in cortisol. In the case of liver injury, metabolism of cortisol was greatly affected and their disappearance from blood decreased markedly. However, such change in the disappearance rate was hardly seen in synthetic steroids and this fact may suggest that enzyme systems that metabolize the special structure of synthetic corticosteroids are not adequately developed in the normal liver. Administration of synthetic corticosteroids to patients of renal insufficiency resulted in the lowering of disappearance rate from blood. Consequently, it Table 1. is certain that disappearance of cortisol from blood is due mainly to its metabolism in the liver while that of its synthetic analogues is partly due to metabolism in the liver but is more strongly affected by excretion from the kidneys. Such excretion from the kidney was characteristic in the case of triamcinolone. Transfer of radioactivity of triamcinolone-3h to the free fraction of urine was far more than that into the conjugate fraction. Table 1 gives comparison of prednisolone-3h and triamcinolone~3h in the
7 Vol. 2, No. 3 METABOLISM AND KINETICS OF STEROIDS 445 effect of liver and kidney on the rate of disappearance from blood, using the foregoing kinetics model for cortisol and interpolating the data of radioactivity transfer into the free fraction of the urine, and calculating the rate constants of metabolism in the body and urinary excretion. Taking K30) as excretion from the kidney and K3(2) as the metabolism in the liver, K3(1) is greater in triamcinolone than prednisolone, while K3(2) is greater in prednisolone than triamcinolone. This indicates that the rate of disappearance of triamcinolone from blood is more greatly affected by the factor of renal function than that of prednisolone. (2) Long-term Administration and Metabolism of Synthetic Derivatives of Cortisol : Changes in metabolism of corticosteroids by long-term administration of adrenocortical hormones will be described. Long-term administration of cortisol is difficult to find in clinical examples and a tracer dose of cortisol-4-14c was injected into a patient of Cushing's syndrome, in which increased secretion of cortisol is considered to be continuing over a long period, to examine its turnover rate. A markedly accelerated secretion (about 60mg./day) was observed, although biological half-time of plasma removal of radioactivity in the free fraction was 90 minutes, which is not markedly different from that in normal subjects. In the case of Addison's disease, in which continued decrease of secretion is expected to be extended over a long period, daily secretion was decreased to 8mg. but no change was seen in the turnover rate (k3). These facts seem to indicate that there is no adaptive change in liver metabolism against increase or decrease of cortisol in the body over a long period and it is noteworthy that this differs markedly from the behavior of corticosteroid metabolism in the liver after long-term administration of synthetic adrenocortical hormones, as will be described below. It was found by the author that a long-term administration of synthetic adrenocortical hormones in various diseases resulted in marked promotion of their disappearance of free fraction from blood at the time of intravenous loading of the hormone. A part of such results is given in Fig. 3 for prednisolone, dexamethasone, and methylprednisolone. An interesting point is that disappearance of cortisol from blood remained normal even during such accelerated
8 446 Araki Jap. J. Med Fig. 3. rate of disappearance of these synthetic corticosteroids after their long-term administration. In order to clarify whether such change in the disappearance of synthetic corticosteroids from blood by a long-term administration is due to accelerated metabolism of the steroids in the liver or to increased excretion from the kidneys, plasma removal rate at the time of intravenous loading was examined with patients of renal insufficiency whohad been receiving synthetic corticosteroid over a long period. This result showed that, in spite of a very small urinary excretion, there was a marked increase in the plasma removal rate of free fraction. On the other hand, in the patients with liver injury, who had been receiving synthetic adrenocortical hormone over a long period, there was no change in the plasma removal rate. This phenomenon, which may be termed a kind of metabolic adaptation of a living body against synthetic corticosteroids, is chiefly being carried out in the liver. Summaryand Discussion Comparison between synthetic corticosteroids and cortisol, the natural hormone, in metabolism and behavior characteristics may be summarized as follows : Synthetic corticosteroids : (1) Plasma removal rate is lower than that of cortisol. (2) Rate of urinary excretion of free type to conjugate type is greater than that of cortisol.
9 Vol. 2, No. 3 METABOLISM AND KINETICS OF STEROIDS 447 (3) Apparent distribution volume is greater than that of cortisol. In other words, the following may be said. (a) Plasma removal rate of the free active form is dependent on the liver function in the case of cortisol but is affected greatly by renal function in the case of synthetic analogues. (b) Synthetic corticosteroids have stronger power than cortisol for dispersion and penetration into the living tissue. Consequently, the difference in the characteristics of metabolism and kinetics between these synthetic corticosteroids and cortisol should be taken into consideration when using adrenocortical hormones for various diseased states handled in the field of internal medicine, in the point of their effect and appearance of side effects. On the other hand, synthetic corticosteroids differ from cortisol, which is produced in the body, in that a phenomenon which may be considered as adaptation to the administered steroid is observed during a long-term administration of synthetic corticosteroids and removal rate of the biologically active free fraction is accelerated. The fact that the effect of synthetic adrenocortical hormones decreases during their continued use may be explained in part from such a phenomenon. This is also important in connection with the question of changing the steroid hormones used during a long-term use. When an accelerated turnover rate occurs during the long-term use of an adrenocortical hormone, how the metabolism of other synthetic corticosteroids would change cannot be stated for certain at the present stage since this point has not been examined with all the known synthetic corticosteroids. It can be said, at least, that accelerated turnover rate was observed in dexamethasoneas well as prednisolone during a long-term administration of prednisolone, and an inverse correlation was also found to exist. Such a phenomenonis probably related to the metabolism of a chemical structure commonto both steroids, i.e. the double bond between carbon atoms 1 and 2. IV. Conclusion In the present series of work, kinetics of endogenous cortisol at the time of stress, and metabolism and biological kinetics of synthetic corticosteroids were clarified. Some re-examinations were
10 448 Araki Jap. J. Med made from the point of corticosteroid therapy and few items that should be considered in such a case were stated. Acknowledgements The author expresses his thanks to Prof. Sadataka Tasaka, the President of the Japanese Society of Internal Medicine, and to Prof. Tatsuo Torikai, the Chairman of the Symposium on the Clinics of Adrenocortical Hormones. He is grateful to Prof. S. Tasaka and Assist. Prof. Y. Yoshitoshi for their guidance and encouragement, and is indebted for the technical cooperation of Drs. Osamu Yokota, Tatsuo Kato, Masaaki Kashima, Tatsuo Miyazaki and Tatsuo Kuwashima. References 1) Araki, Y.: Igakuno Ayumi 23: , ) Flood, C. et al.: Acta Endocrinol. 36: , ) Florini, J.R. et al.: J. Pharmacol. 131: , ) Gray,C.H. and Bachrach,A.L. (eds) : Hormones inblood,newyork andlondon, Academic Press ) Laumas, K.R. et al.: Acta Endocrinol. 36: , ) Peterson, R.E.: Recent Progress in Hormone Research 15: , ) Sandberg, A.A. and Slaunwhite, W.R.: J. Clin. Endocrinol. & Metab. 17: 1050, ) Tait, J.F. et al.: J. Clin. Invest. 40: 72-80, ) Tamm, J. and Voigt, K.: Acta endocrinol. Suppl. 54: 5-80, 1961.
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