N-carbamylglutamate augments ureagenesis and reduces ammonia and glutamine in propionic acidemia

Abstract

Objectives: The objective of this study was to determine whether N-carbamylglutamate (NCG) reduces plasma levels of ammonia and glutamine and increases the rate of ureagenesis in patients with propionic acidemia (PA).

Methods: Identical 4-hour studies were performed before and immediately after a 3-day trial of oral NCG in 7 patients with PA. An oral bolus of [(13)C]sodium acetate was administered at the start of each study, and sequential blood samples were obtained to measure [(13)C]urea, ammonia, urea, and amino acids.

Results: With longitudinal mixed-effects linear regression, peak [(13)C]urea increased after treatment with NCG (from 2.2 to 3.8 microM; P < .0005). There were concomitant decreases in mean plasma ammonia (59-43 microM; P < .018) and glutamine (552-331 microM; P < .0005).

Conclusions: NCG augments ureagenesis and decreases plasma ammonia and glutamine in patients with PA. The drug may serve as an important therapeutic adjunct in the treatment of acute hyperammonemia in this disorder.

Figures

Figure 1

Overall trial timeline. Identical studies were performed before (‘day 1’) and immediately following (‘day 4’) a 3-day course of N-carbamylglutamate at a dose of 100 mg/kg/d or 2.2g/m2/d if ≥25 kg. Plasma samples for ammonia, urea, amino acids and [13C]urea were obtained at T0, 15, 30, 45, 60, 90, 120, 180, and 240 min.

Figure 2

Isotopic enrichment in plasma 13CO2 (A), and [13C]urea (B) in 7 subjects with propionic acidemia who were administered 27.5 mg/kg of [1-13C]sodium-acetate. Results are model estimates +/- 95% CI. Subject 4 contributes to mean data only at time-points 0, 15, 30, 60 and 120 minutes.

Figure 2

Isotopic enrichment in plasma 13CO2 (A), and [13C]urea (B) in 7 subjects with propionic acidemia who were administered 27.5 mg/kg of [1-13C]sodium-acetate. Results are model estimates +/- 95% CI. Subject 4 contributes to mean data only at time-points 0, 15, 30, 60 and 120 minutes.

Figure 3

Plasma levels of ammonia (A), glutamine (B), alanine (C), glycine (D) and urea (E) in 7 patients with propionic acidemia before and following a 3-day treatment with N-carbamylglutamate. Mean values +/- 95% CI are shown in bold. 1Based on log transformation; 2Based on square root transformation