To determine whether circulating citrulline can be manipulated in vivo in humans, and, if so, whether citrulline availability affects the levels of related amino acids, nitric oxide, urinary citrulline, and urea nitrogen, 10 healthy volunteers were studied on 3 separate days: 1) under baseline conditions; 2) after a 24-h treatment with phenylbutyrate (0.36 g.kg(-1).day(-1)), a glutamine "trapping" agent; and 3) during oral L-citrulline supplementation (0.18 g.kg(-1).day(-1)), in randomized order. Plasma, erythrocyte (RBC), and urinary citrulline concentrations were determined by gas chromatography-mass spectrometry at 3-h intervals between 1100 and 2000 on each study day. Regardless of treatment, RBC citrulline was lower than plasma citrulline, with an RBC-to-plasma ratio of 0.60 +/- 0.04, and urinary citrulline excretion accounted for <1% of the citrulline load filtered by kidney. Phenylbutyrate induced an approximately 7% drop in plasma glutamine (P = 0.013), and 18 +/- 14% (P < 0.0001) and 19 +/- 17% (P < 0.01) declines in plasma and urine citrulline, respectively, with no alteration in RBC citrulline. Oral L-citrulline administration was associated with 1) a rise in plasma, urine, and RBC citrulline (39 +/- 4 vs. 225 +/- 44 micromol/l, 0.9 +/- 0.3 vs. 6.2 +/- 3.8 micromol/mmol creatinine, and 23 +/- 1 vs. 52 +/- 9 micromol/l, respectively); and 2) a doubling in plasma arginine level, without altering blood urea or urinary urea nitrogen excretion, and thus enhanced nitrogen balance. We conclude that 1) depletion of glutamine, the main precursor of citrulline, depletes plasma citrulline; 2) oral citrulline can be used to enhance systemic citrulline and arginine availability, because citrulline is bioavailable and very little citrulline is lost in urine; and 3) further studies are warranted to determine the mechanisms by which citrulline may enhance nitrogen balance in vivo in humans.

. (1974). Archives of Disease in Childhood, 49, 553. Detection of heterozygotes for homocystinuria: study of sulphur-containing amino acids in plasma and urine after L-methionine loading. Twelve parents of patients with homocystinuria and 12 normal control subjects were given standard L-methionine loads. Determination of plasma concentrations of homocystine and cysteine-homocysteine disulphide, of urine concentration ratios of homocystine: cystine, cysteine-homocysteine disulphide : cystine, and homocysteic acid: cysteic acid allowed a distinction to be made between the two groups. The findings indicate the value of the L-methionine loading test for detection of heterozygotes for homocystinuria, particularly where facilities for fibroblast culture and cystathionine synthase assay are not available.It has been shown that heterozygotes for homocystinuria have approximately half the normal cystathionine synthase activity in liver biopsy specimens (Finkelstein et al., 1964). This reduced ability of heterozygotes to metabolize methionine has been tested by a number of investigators in order to devise a test for the carrier state in this condition.Brenton, Cusworth, and Gaull (1965) loaded 2 parents of affected children and 3 normal adult male controls with L-methionine (0 -1 g/kg body weight). Measurement of sulphur amino acids in blood and urine revealed no conclusive differences between the parents and normal subjects. Similar observations were made by Kennedy, Shih, and Rowland (1965) and White et al. (1964). Laster et al. (1965) administered a single oral dose of L-methionine to parents who had been shown to have reduced activity of cystathionine synthase in liver biopsy specimens. Measurement of inorganic sulphate excretion during the post-load period failed to distinguish between the parents and 5 control subjects, even when the dose was varied between approximately 0 c 1 and 0 5 mmol L-methionine/kg body weight. Dunn, Perry, and Dolman (1966) measured plasma methionine concentrations in 4

A preliminary survey showed that many outpatients with partially controlled epilepsy had serum concentrations of phenytoin below the recommended therapeutic range (10-20 jig/ml 3.8,g/ml. The mean calculated dose of phenytoin sodium required for a steady state serum concentration of 10-20 ,ug/ml was 345-400 mg/day. 4 The Michaelis-Menten principle was used to predict steady state serum phenytoin concentrations in individual patients receiving daily doses of phenytoin sodium adjusted by steps of 100 mg. The serum concentrations tended to be either too low or too high. The steep relationship between phenytoin concentration and dose indicates that when the concentration reaches 5-10 Mg/ml it is then appropriate to adjust dose by small steps of about 25 mg.

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