Effects of a single dose of N-carbamylglutamate on the rate of ureagenesis

Abstract

We studied the effect on ureagenesis of a single dose of N-carbamylglutamate (NCG) in healthy young adults who received a constant infusion (300 min) of NaH(13)CO(3). Isotope ratio-mass spectrometry was used to measure the appearance of label in [(13)C]urea. At 90 min after initiating the H(13)CO3-infusion each subject took a single dose of NCG (50 mg/kg). In 5/6 studies the administration of NCG increased the formation of [(13)C]urea. Treatment with NCG significantly diminished the concentration of blood alanine, but not that of glutamine or arginine. The blood glucose concentration was unaffected by NCG administration. No untoward side effects were observed. The data indicate that treatment with NCG stimulates ureagenesis and could be useful in clinical settings of acute hyperammonemia of various etiologies.

Figure 1

Isotopic abundance (atom % excess) in ¹³CO₂ in expired air in healthy adults who received an infusion of NaH¹³CO₃ (0.089 mmol/kg/hr; 98 atom % excess) for a period of 300 minutes. The solid horizontal line denotes the mean isotopic abundance from 10 to 300 minutes. During the initial 10 minutes of the experiment each subject also received a priming dose (0.083 mmol/kg) of the labeled bicarbonate. Breath was taken at the times indicated by having each individual exhale into a plastic collection device fitted with a one-way valve. At 90 minutes each individual received an oral dose of NCG (100 mg/kg).

Fig. 2

The concentration of [¹³C]urea in plasma during the constant infusion of NaH¹³CO₃ (Fig. 1) in healthy adults. The line represents linear regression analysis from 10 to 150 minutes. At 90 minutes each subject received an oral dose (50 mg/kg) of NCG. The closed circles correspond to the period during which the linear regression was performed. The open circles are points from 150 until 300 minutes and correspond to the post-treatment values. The time from 10 until 150 minutes is included in the regression because this is a period of drug absorption. The number at the top of each graph(µmol/min/liter) correspond to the rate of [¹³C]urea appearance in blood. Calculation was done as explained above (Methods).

Fig. 3

Plasma amino acid levels (mean ± SEM) for the 6 studies in healthy volunteers. The data are expressed as a percentage of the baseline T₀) value in order to facilitate comparison. The arrow denotes an oral dose (50 mg/kg) of NCG, taken in an aqueous solution. As noted (Results), significant (p < .05) changes in concentration post-NCG were observed with regard to the concentration of alanine and of isoleucine.

Fig. 4

Blood glucose concentration (mmol/l; mean ± SEM) for the 6 studies. The arrow denotes the time (90 min) of administration of NCG (50 mg/kg).