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Plasma kinetics and metabolism of labeled dexamethasone were evaluated in nine subjects before and after administration of diphenylhydantoin. Labeled dexamethasone was injected intravenously followed by frequent sampling of blood and urine. The labeled dexamethasone in plasma was isolated chromatographically. Total urine and fractional radioactivity after solvent extraction (chloroform and ethyl acetate), with and without glucuronide hydrolysis, were determined. Baseline plasma equilibrated tj4's and metabolic clearance rates (2 compartment model) ranged from 167 to 368 minutes and 222 to 456 liters/day, respectively. After diphenylhydantoin there were consistent decreases in t j^ and increases in metabolic clearance rate; mean changes -5 1 % and -f-140% respectively.Mean recovery of urinary radioactivity at 4 and 24 hours was 16 and 64 percent of dose respectively. The largest fraction was a more polar unconjugated one, 7 and 31 percent of dose at 4 and 24 hours. Following diphenylhydantoin there was a significant increase in rate of appearance of radioactivity in urine, the greatest increase being in the more polar unconjugated fraction.It is concluded that 1) the metabolic kinetics of plasma dexamethasone vary considerably among individuals and 2) diphenylhydantoin administration markedly hastens removal rate of dexamethasone from plasma mainly by increasing conversion to more polar metabolites. ( / Clin Endocr 34: 44, 1972) A LTHOUGH synthetic glucocorticoids have been employed clinically for several years little attention has been given to their metabolism. Our interest in this problem developed a few years ago when it was noted that diphenylhydantoin (DPH) inhibited the effectiveness of dexamathasone during standard plasma dexamethasone suppression tests (1). The current report describes studies of plasma disappearance and metabolic clearance rates of circulating labeled dexamethasone, of rate of appearance of radioactivity in urine fractions and of the manner in which DPH affects these measurements.Jubiz et al. have reported on certain aspects of this problem (2). It was demon-

During a study of cortisol metabolism in advanced cancer and other disease states (1), we observed in patients receiving DPH 1 therapy for convulsive seizures an abnormal pattern of excretion of cortisol metabolites in urine. This abnormal pattern was characterized by increased urinary output of the polar unconjugated metabolite 6-OHF, suggesting an interference with extraadrenal metabolism of cortisol by DPH. We =5,5'-diphenylhydantoin; 6-hydroxycortisol (6 -OHF) = 6a (/3), 11,/, 17a, 21 -tetrahydroxy -4 -pregnene-3,20 -dione; 17-OHCS = 17-hydroxycorticosteroids; ACTH = adrenocorticotrophic hormone; methopyrapone (Metopirone, Ciba Pharmaceutical Co., Summit, N. J.) =2-methyl-1,2-di-(3-pyridyl)-1-propanone. Tetrahydro derivatives: THF (tetrahydrocortisol) = 3a,11,, 17a,21-tetrahydroxy-5/8-pregnan-20-one; allo-THF (allotetrahydrocortisol) = 3a,11/3,17a,21-tetrahydroxy-5a-?pregnan-20-one; THE (tetrahydrocortisone) = 3a,17a,21-trihydroxy-5p-pregnan-11,20-dione. Cortol = 3a,11,8,17a,20a (/3),21-pentahydroxy-5/3-pregnane; cortolone = 3a,17a,20a (/3) ,21-tetrahydroxy-5/8-pregnan-11-one; 17-KS = 17-ketosteroids; 1 1-hydroxyetiocholanolone = 3a,1j1/-dihydroxy-5,B-androstan-17-one; dehydroisoandrosterone = 3/3-hydroxy-5-androstene-17-one; TPNH = reduced triphosphopyridine nucleotide; o,p'DDD = 2,2-bis (2-chlorophenyl,4-chlorophenyl) 1,1-dichloroethane. since a) adrenal hypertrophy was observed in intact rats and b) in adrenalectomized rats treated with DPH a more profound decrease in brain excitability was demonstrated than in intact rats. Goncharov has observed that acute administration of DPH to dogs and guinea pigs increases adrenocortical output of cortisol (3). Reports by Staple (4) and Bonnycastle and Bradley (5) have, however, indicated an inhibition of pituitary-adrenal secretion after chronic DPH treatment of mice and rats.In humans also cortisol has been shown to enhance brain excitability (6). After chronic DPH therapy to patients, excretion of corticosteroids in urine is reported to decrease (7, 8) after an initial increase (7). These findings have led to the suggestion that the decrease in brain excitability induced by DPH might be mediated partially through adrenocortical suppression. However, levels of 17-OHCS in plasma from patients treated with DPH are usually normal (8, 9), as are responses to ACTH (8, 9) and rates of disappearance from plasma of infused cortisol (8). These observations detract from the possibility that direct adrenocortical suppression plays a significant role in therapeutic effectiveness of DPH. Recently, however, Krieger has demonstrated that control subjects treated with DPH manifest a reduced response in the methopyrapone test, which suggests an interference with ACTH release (10).2) The increased excretion of 6-OHF produced by DPH appears to be similar to that we have observed in patients with advanced cancer and certain terminal illnesses (1) as well as to that reported after estrogen therapy (11), during pregnancy (12), and in newborn infants (13).Thus we hoped that furthe...

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The phenomenon of ketosis has interested investigators and clinicians for many years. With the recent rapid strides in the understanding of fat metabolism and the central role of acetyl-CoA in intermediary metabolism (1-5), this subject has taken on added interest. Although it has long been recognized that the liver is the chief site of origin of the ketone bodies, the basis for this has only recently been clarified. Apparently, most tissues are capable of forming acetoacetyl-CoA during the normal course of fatty acid catabolism or by condensation of two molecules of acetylCoA, but only the liver both possesses an enzyme, deacylase, which removes CoA from the molecule to release free acetoacetate, and at the same time lacks the acetoacetate activating enzyme which would result in acetoacetate's re-entering the metabolic cycle as acetoacetyl-CoA. Other tissues have some deacylase activity, but their acetoacetate activating enzyme system is so active that little or no free acetoacetate ever escapes from the cell (4). Ketonemia thus represents the balance between the rate of ketone production by the liver, utilization by extra hepatic tissues and excretion by the kidneys. Hepatic ketone production in turn is a function of the relative rates at which acetyl-CoA and acetoacetyl-CoA are formed, as from fat catabolism, and amino acids, and the rate at which acetyl-CoA can be disposed of by oxidation via the Krebs cycle or by reduction and syn-1