Chemical formula: C₆H₁₀N₂O₅ Molecular mass: 190.154 g/mol PubChem compound: 121396
Carglumic acid is a structural analogue of N-acetylglutamate, which is the naturally occurring activator of carbamoyl phosphate synthetase, the first enzyme of the urea cycle.
Carglumic acid has been shown in vitro to activate liver carbamoyl phosphate synthetase. Despite a lower affinity of carbamoyl phosphate synthetase for carglumic acid than for N-acetylglutamate, carglumic acid has been shown in vivo to stimulate carbamoyl phosphate synthetase and to be much more effective than N-acetylglutamate in protecting against ammonia intoxication in rats.
This could be explained by the following observations:
Other studies have been conducted in rats under different experimental conditions leading to increased ammonia availability (starvation, protein-free or high-protein diet). Carglumic acid was shown to decrease blood ammonia levels and increase urea levels in blood and urine, whereas the liver content of carbamoyl phosphate synthetase activators was significantly increased.
The pharmacokinetics of carglumic acid has been studied in healthy male volunteers using both radiolabelled and unlabelled product.
After a single oral dose of 100 mg/kg body weight, approximately 30% of carglumic acid is estimated to be absorbed. At that dose-level, in 12 volunteers given carglumic acid tablets, plasma concentration peaked at 2.6 μg/ml (median; range 1.8-4.8) after 3 hours (median; range 2-4).
The plasma elimination curve of carglumic acid is biphasic with a rapid phase over the first 12 hours after administration followed by a slow phase (terminal half life up to 28 hours). Diffusion into erythrocytes is non existent. Protein binding has not been determined.
A proportion of carglumic acid is metabolised. It is suggested that depending on its activity, the intestinal bacterial flora may contribute to the initiation of the degradation process, thus leading to a variable extent of metabolism of the molecule. One metabolite that has been identified in the faeces is glutamic acid. Metabolites are detectable in plasma with a peak at 36-48 hours and a very slow decline (half-life around 100 hours).
The end product of carglumic acid metabolism is carbon dioxide, which is eliminated through the lungs.
After a single oral dose of 100 mg/kg body weight, 9% of the dose is excreted unchanged in the urine and up to 60% in the faeces.
Plasma levels of carglumic acid were measured in patients of all age categories, from newborn infants to adolescents, treated with various daily doses (7–122 mg/kg/day). Their range was consistent with those measured in healthy adults, even in newborn infants. Whatever the daily dose, they were slowly declining over 15 hours to levels around 100 ng/ml.
Safety pharmacology studies have shown that carglumic acid administered orally at doses of 250, 500, 1000 mg/kg had no statistically significant effect on respiration, central nervous system and cardiovascular system.
Carglumic acid showed no significant mutagenic activity in a battery of genotoxicity tests performed in vitro (Ames test, human lymphocyte metaphase analysis) and in vivo (micronucleus test in rat).
Single doses of carglumic acid up to 2800 mg/kg orally and 239 mg/kg intravenously did not induce any mortality or abnormal clinical signs in adult rats. In newborn rats receiving daily carglumic acid by oral gavage for 18 days as well as in young rats receiving daily carglumic acid for 26 weeks, the No Observed Effect Level (NOEL) was established at 500 mg/kg/day and the No Observed Adverse Effect Level (NOAEL) was established at 1000 mg/kg/day.
No adverse effects have been observed on male or female fertility. In rats and rabbits no evidence has been seen of embryotoxicity, foetotoxicity or teratogenicity up to maternotoxic doses leading to fifty times exposure as compared to humans in rats and seven times in rabbits. Carglumic acid is secreted in the milk of lactating rats and although developmental parameters were unaffected, there were some effects on body weight/body weight gain of pups breast-fed by dams treated with 500 mg/kg/day and a higher mortality of pups from dams treated with 2000 mg/kg/day, a dose that caused maternotoxicity. The maternal systemic exposures after 500 and 2000 mg/kg/day were twenty five times and seventy times the expected human exposure.
No carcinogenicity study has been conducted with carglumic acid.
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