A B S T R A C T Sodium phenobarbital and various hormones, compounds capable of hepatic enzyme induction, were given to an infant boy with congenital, nonhemolytic, unconjugated, hyperbilirubinemia and severe kernicterus for prolonged periods between the ages of 2 and 25 months to determine their effect on serum bilirubin concentrations. Phenobarbital, 5 mg/day orally, on two occasions decreased serum bilirubin concentrations approximately threefold over a period of 30 days. Withdrawal of phenobarbital after the first study resulted in a gradual (30 days) return of serum bilirubin to pretreatment levels. The lower serum bilirubin concentrations observed when phenobarbital therapy was reinstituted were maintained for 61 days on 2.5 mg/kg per day of the drug. Orally administered L-triiodothyronine, 0.05-0.1 mg/day for 71 days, intramuscular human growth hormone, 1 mg/day for 21 days, and testosterone propionate, 0.1 mg/day for 9 days, did not decrease serum bilirubin levels below lowest control values of 18 mg/100 ml.Bilirubin-'H was administered twice before and once with bilirubin-"C during phenobarbital therapy to study the kinetics of bilirubin metabolism. Results of the first and second control studies and of the bilirubin-'H and bilirubin-"C phenobarbital studies, respectively, were as follows: tptal body bilirubin pools, 200, 184, 73, and 72 mg; half-lives, 111, 84, 37, and 39 hr; and turnover, 30, 37, 33, and 31 mg/day. The data show that the ap- tration and total body pool resulted from a comparable decrease in bilirubin half-life without a significant change in turnover.In vitro histological (electron microscopy) and enzymological studies of liver obtained by surgical biopsies before and during phenobaribtal administration showed that both the hepatocyte content of agranular endoplasmic reticulum (AER) and the ability of liver homogenate to conjugate p-nitrophenol were significantly increased during phenobarbital treatment.The observations suggest that phenobarbital affects bilirubin metabolism by the induction of an enzyme(s) with a slow rate(s) of degradation (or rapid rate of degradation with limited capacity).

Variations have been shown to occur in the quantitative urinary excretion pattern of the metabolites of cortisol in a variety of traumatic events such as surgery, bone fracture and burns (1). The compounds evaluated were THF, allo-THF and THE,' and it was demonstrated that the relative proportion of THF: THE excreted during and after a "traumatic event" was markedly increased. In addition almost complete absence of allo-THF was observed in a chronically ill individual and it reappeared upon convalescence. The rate of secretion of cortisol was one factor involved in producing the increase in urinary THF: THE, since following the administration of adrenocorticotropin (ACTH) to normal individuals the relative proportion of urinary THF as compared with THE was observed to rise (1)(2)(3)(4)(5) factors other than the rate of adrenal secretion were involved in altering the rates of excretion of the numerous metabolites of cortisol. It became clear that knowledge concerning the pathways of metabolism, the pool sizes of the metabolites and the relative rates of formation of the individual metabolites from cortisol would prove valuable in interpreting the urinary excretion patterns of these compounds.2 Consequently these studies were undertaken to determine the extent of the reaction THF = THE in volunteer subjects with and without the administration of ACTH; the pathways for the formation of THF, allo-THF, THE and cortolone from cortisol; the miscible pool size of THF, allo-THF, THE and cortolone; and the possibility of determining the overall rates of formation of THF, allo-THF and THE. This work was performed in volunteer subjects with cortisol-4-C14 as a tracer. METHODSGeneral plan. Tracer doses of cortisol4-C' (1 puc., about 250 ,ug.) were administered intravenously to normal volunteer subjects and urine samples were collected every 15 minutes. The specific activity of cortisol and its metabolites was determined as a function of time, and pool sizes and pathways were determined by isotope dilution procedures after the intravenous administration of small amounts of unlabeled cortisol metabolites. The rates of formation of these metabolites were computed in several instances using the criteria described by Zilversmit, Entenman and Fishler (6

Methods for the quantitative estimation of plasma cortisol concentration have been devised by Nelson and Samuels (1), Silber and Porter (2), and Peterson and Wyngaarden (3) who used the sulfuric acid-induced fluorescence developed by Sweat (4). Together with urinary procedures (5, 6) these techniques have been employed to determine the secretion of cortisol by the adrenal in normal and pathological conditions (7-9) and to evaluate the factors involved in the "removal" of cortisol from the plasma in surgery (10-13) and liver disease (14-16).Although a considerable amount of work has been done in isolating and identifying such urinary metabolites of cortisol as THF8 and THE (17-22) and their interconversions (23-25), much less has been done to relate the quantitative transformations of these urinary metabolites from cortisol under normal and pathological conditions. In 1953, deCourcy, Bush, Gray, and Lunnon (26) reported daily excretion values for two chromatographically separated urinary steroids corresponding in migration rates to THF and THE, in 10 1 This work was suported in part by a grant from the Atomic Energy Commission. It was sponsored and supported in part by the Subcommittee on Metabolism in Trauma, Advisory Committee on Metabolism, Office of the Surgeon General, Department of the Army, through a contract (DA-49-MD472) with Harvard University.The assistance of Winthrop Laboratories, Inc., and The Upjohn Co. is gratefully acknowledged.2 Present address: The Medical College of St. Bartholomew's Hospital, London. 3 Compounds referred to are the following: THF, tetrahydrocortisol (3a,11p,17a,21-tetrahydroxypregnan-20-one ); allo-THF (3a,1 1,l17a,21-tetrahydroxyallopregnan-20-one); THE, tetrahydrocortisone (3a,17a,21-trihydroxypregnan-11,20-dione); F, cortisol (llfi,17a,21-trihydroxypregnan-3,20-dione); E, cortisone (17a,21-dihydroxypregnan-3,11,20-trione).normal men. The mean values were 212 tg. per 24 hours for THF and 1.5 mg. per 24 hours for THE, giving a ratio for THF: THE of 0.14. Romanoff, Seelye, Rodriquez, and Pincus (27) have recently published quantitative data on the excretion of THF and THE combined with allo-THF (28, 29) in one group of normal men and in a group of schizophrenic men. There was no essential difference in the ratio of THF:(THE plus allo-THF) between the two groups of men, and the ratio was reported as approximately 1: 2. Cope and Hurlock (30) published data on the excretion of urinary THF and THE in several normal and surgical cases. Their results indicated increased excretion of these metabolites after surgery but did not show any other definite pattern of alteration of the metabolism of cortisol, although they state that "a tendency can be observed for tetrahydro-compound F excretion to rise more than does tetrahydrocortisone." In a preliminary report, Gold, Macfarlane, and Moore (31) showed that the relative proportions of the two urinary cortisol metabolites, THF and THE, were related to situations of "stress" and adrenocorticotropin (ACTH) administration. It is the purpo...

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