Carglumic acid is an orphan drug used for the treatment of hyperammonaemia in patients with N-acetylglutamate synthase deficiency. This rare genetic disorder results in elevated blood levels of ammonia, which can eventually cross the blood–brain barrier and cause neurologic problems, cerebral edema, coma, and death. Carglumic acid was approved by the U.S. Food and Drug Administration (FDA) on 18 March 2010.
|External IDs||OE 312 / OE-312|
|Product Ingredients||Not Available|
|Approved Prescription Products|
|Approved Generic Prescription Products||Not Available|
|Approved Over the Counter Products||Not Available|
|Unapproved/Other Products||Not Available|
|International Brands||Not Available|
|Brand mixtures||Not Available|
|Weight||Average: 190.154 |
For the treatment of acute and chronic hyperammonaemia in patients with N-acetylglutamate synthase (NAGS) deficiency. This enzyme is an important component of the urea cycle to prevent build up of neurotoxic ammonium in the blood.
The median Tmax of Carbaglu was 3 hours (range: 2-4). The initial daily dose ranges from 100 to 250 mg/kg, adjusted thereafter to maintain normal plasma levels of ammonia.
|Mechanism of action|
Carglumic acid is a synthetic structural analogue of N-acetylglutamate (NAG), which is an essential allosteric activator of the liver enzyme carbamoyl phosphate synthetase 1 (CPS1). CPS1 is found in the mitochondria and is the first enzyme of the urea cycle, which converts ammonia into urea. Carglumic acid acts as a replacement for NAG in NAGS deficiency patients by activating CPS1 but it does not help to regulate the urea cycle.
Cmax, mean, 100 mg/kg dose = 2.6 μg/mL (range of 1.9 - 4.8)
|Volume of distribution|
The apparent volume of distribution was 2657 L (range: 1616-5797).
|Protein binding||Not Available|
A proportion of carglumic acid may be metabolized by the intestinal bacterial flora. The likely end product of carglumic acid metabolism is carbon dioxide, eliminated through the lungs.
|Route of elimination|
Following administration of a single radiolabeled oral dose of 100 mg/kg of body weight, 9% of the dose was excreted unchanged in the urine and up to 60% of the dose was excreted unchanged in the feces.
Median values for the terminal half-life was 5.6 hours (range 4.3-9.5).
The apparent total clearance was 5.7 L/min (range 3.0-9.7), the renal clearance was 290 mL/min (range 204-445), and the 24-hour urinary excretion was 4.5 % of the dose (range 3.5-7.5).
LD50, oral, mouse: >1000 mg/kg
|Pharmacogenomic Effects/ADRs||Not Available|
|Drug Interactions||No interactions found.|
|Food Interactions||Not Available|
|Synthesis Reference||Not Available|
|ATC Codes||A16AA05 — Carglumic acid|
|PDB Entries||Not Available|
|FDA label||Download (351 KB)|
|MSDS||Download (82.3 KB)|
|Predicted ADMET features|
|Mass Spec (NIST)||Not Available|
|Description||This compound belongs to the class of chemical entities known as glutamic acid and derivatives. These are compounds containing glutamic acid or a derivative thereof resulting from reaction of glutamic acid at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.|
|Super Class||Organic compounds|
|Class||Organic acids and derivatives|
|Sub Class||Carboxylic acids and derivatives|
|Direct Parent||Glutamic acid and derivatives|
|Alternative Parents||Fatty acids and conjugates / Dicarboxylic acids and derivatives / Isoureas / Carboxylic acids / Carboximidamides / Organopnictogen compounds / Organic oxides / Imines / Hydrocarbon derivatives / Carbonyl compounds|
|Substituents||Glutamic acid or derivatives / Dicarboxylic acid or derivatives / Fatty acid / Isourea / Carboximidamide / Carboxylic acid / Carboximidic acid derivative / Organic oxide / Organic nitrogen compound / Hydrocarbon derivative|
|Molecular Framework||Aliphatic acyclic compounds|
|External Descriptors||ureas, N-acyl-L-glutamic acid (CHEBI:71028 )|
- Pharmacological action
- allosteric modulator
- General Function:
- Phospholipid binding
- Specific Function:
- Involved in the urea cycle of ureotelic animals where the enzyme plays an important role in removing excess ammonia from the cell.
- Gene Name:
- Uniprot ID:
- Uniprot Name:
- Carbamoyl-phosphate synthase [ammonia], mitochondrial
- Molecular Weight:
- 164938.145 Da
- Authors unspecified: Carglumic acid: a second look. Confirmed progress in a rare urea cycle disorder. Prescrire Int. 2008 Apr;17(94):50-1. [PubMed:18516804 ]
- Hart EJ, Powers-Lee SG: Role of Cys-1327 and Cys-1337 in redox sensitivity and allosteric monitoring in human carbamoyl phosphate synthetase. J Biol Chem. 2009 Feb 27;284(9):5977-85. doi: 10.1074/jbc.M808702200. Epub 2008 Dec 23. [PubMed:19106093 ]
- Kasapkara CS, Ezgu FS, Okur I, Tumer L, Biberoglu G, Hasanoglu A: N-carbamylglutamate treatment for acute neonatal hyperammonemia in isovaleric acidemia. Eur J Pediatr. 2011 Jun;170(6):799-801. doi: 10.1007/s00431-010-1362-9. Epub 2011 Jan 5. [PubMed:21207059 ]