Effect of Diphenylhydantoin on Cortisol Metabolism in Man *

Abstract

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...

D‐glucaric acid excretion in critical care patients‐comparison with 6 beta‐hydroxycortisol excretion and serum gamma‐glutamyltranspeptidase activity and relation to multiple drug therapy.

“…This might be due to increased cortisol production as a result ofstress (Finlay & McKee, 1982). Further, Frantz et al (1960) and Werk et al (1964) (Table 3) exhibiting 6f-OHF values exceeding the upper normal limit did not differ from the patients without administration of known inducers. The 17-OHCS fraction was extremely high (presumably due to extreme stress) and led to as low values in the ratio of 6P-OHF/17-OHCS as found in healthy control persons.…”

Assessment of the drug metabolism capacity of the liver.

“…The net increase in cortisol 6,3-hydroxylation is accompanied by a relative decrease in the production of conjugated, tetrahydro-derivatives of cortisol (Werk et al, 1964).…”

Assessment of urinary 6 beta‐hydroxycortisol as an in vivo index of mixed‐function oxygenase activity.

“…The net increase in cortisol 6,8-hydroxylation is accompanied by a relative decrease in the production of conjugated, tetrahydro-derivatives of cortisol (Werk, MacGee & Sholiton, 1964).…”