Identification
- Summary
Carglumic acid is an analog of N-acetylglutamate (NAG) used for the treatment of acute and chronic hyperammonemia in patients with N-acetylglutamate synthase (NAGS) deficiency.
- Brand Names
- Carbaglu
- Generic Name
- Carglumic acid
- DrugBank Accession Number
- DB06775
- Background
Carglumic acid is a drug used for the treatment of hyperammonemia in patients with a deficiency in N-acetyl glutamate synthase. 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.
- Type
- Small Molecule
- Groups
- Approved
- Structure
Structure for Carglumic acid (DB06775)
- Weight
- Average: 190.154
Monoisotopic: 190.05897144 - Chemical Formula
- C6H10N2O5
- Synonyms
- (2S)-2-(carbamoylamino)pentanedioic acid
- (S)-2-ureidopentanedioic acid
- Acide carglumique
- ácido carglúmico
- Acidum carglumicum
- Carbamino-L-glutamic acid
- Carbamylglutamic acid
- Carglumic acid
- L-N-Carbamoylglutamic acid
- N-Carbamoyl-L-Glutamic Acid
- N-Carbamyl-L-glutamate
- N-Carbamylglutamate
- Ureidoglutaric acid
- External IDs
- OE 312
- OE-312
Pharmacology
- Indication
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.
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- Associated Therapies
- Contraindications & Blackbox Warnings
Avoid life-threatening adverse drug eventsImprove clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events & improve clinical decision support.- Pharmacodynamics
The median Tmax of Carbaglu was 3 hours (range: 2-4). The daily dose of carglumic acid ranges from 100 to 250 mg/kg and this does are normally adjusted 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.
Target Actions Organism ACarbamoyl-phosphate synthase [ammonia], mitochondrial allosteric modulatorHumans - Absorption
30% bioavailability; Cmax, mean, 100 mg/kg dose = 2.6 μg/mL (range of 1.9 - 4.8)
Carglumic acid is not subject to to intracellular degradation.- Volume of distribution
The apparent volume of distribution was 2657 L (range: 1616-5797).
- Protein binding
Not Available
- Metabolism
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.
- Half-life
Median values for the terminal half-life was 5.6 hours (range 4.3-9.5).
- Clearance
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).
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
LD50, oral, mouse: >1000 mg/kg
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.No interactions found.
- Food Interactions
- Take before a meal. Take carglumic acid right before eating.
- Take with plain water. Carglumic acid tablets are dispersed in water to produce an oral suspension and should not be swallowed whole.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Carbaglu Tablet, for suspension 200 mg Oral Recordati Rare Diseases 2016-09-08 Not applicable EU 
Carbaglu Tablet, for suspension 200 mg Oral Recordati Rare Diseases 2016-09-08 Not applicable EU Carbaglu Tablet, for suspension 200 mg Oral Recordati Rare Diseases 2015-09-08 Not applicable Canada 
Carbaglu Tablet, for suspension 200 mg Oral Recordati Rare Diseases 2016-09-08 Not applicable EU Carbaglu Tablet, for suspension 200 mg/1 Oral Recordati Rare Diseases 2010-03-18 Not applicable US 
Ucedane Tablet, for suspension 200 mg Oral Eurocept International Bv 2020-12-16 Not applicable EU Ucedane Tablet, for suspension 200 mg Oral Eurocept International Bv 2020-12-16 Not applicable EU - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Carglumic acid Tablet, for suspension 200 mg/1 Oral Navinta Llc 2022-08-01 Not applicable US Carglumic Acid Tablet, for suspension 200 mg/1 Oral Eton Pharmaceuticals, Inc. 2021-12-20 Not applicable US Carglumic acid Tablet, for suspension 200 mg/1 Oral Burel Pharmaceuticals, Llc 2022-12-19 Not applicable US Carglumic Acid Tablet, for suspension 200 mg/1 Oral Novitium Pharma Llc 2021-10-13 Not applicable US
Categories
- ATC Codes
- A16AA05 — Carglumic acid
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds 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.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Carboxylic acids and derivatives
- Sub Class
- Amino acids, peptides, and analogues
- 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
- Aliphatic acyclic compound / Carbonyl group / Carboximidamide / Carboximidic acid derivative / Carboxylic acid / Dicarboxylic acid or derivatives / Fatty acid / Glutamic acid or derivatives / Hydrocarbon derivative / Imine
- Molecular Framework
- Aliphatic acyclic compounds
- External Descriptors
- ureas, N-acyl-L-glutamic acid (CHEBI:71028)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 5L0HB4V1EW
- CAS number
- 1188-38-1
- InChI Key
- LCQLHJZYVOQKHU-VKHMYHEASA-N
- InChI
- InChI=1S/C6H10N2O5/c7-6(13)8-3(5(11)12)1-2-4(9)10/h3H,1-2H2,(H,9,10)(H,11,12)(H3,7,8,13)/t3-/m0/s1
- IUPAC Name
- (2S)-2-(carbamoylamino)pentanedioic acid
- SMILES
- NC(=O)N[C@@H](CCC(O)=O)C(O)=O
References
- General References
- Elpeleg O, Shaag A, Ben-Shalom E, Schmid T, Bachmann C: N-acetylglutamate synthase deficiency and the treatment of hyperammonemic encephalopathy. Ann Neurol. 2002 Dec;52(6):845-9. [Article]
- Caldovic L, Morizono H, Daikhin Y, Nissim I, McCarter RJ, Yudkoff M, Tuchman M: Restoration of ureagenesis in N-acetylglutamate synthase deficiency by N-carbamylglutamate. J Pediatr. 2004 Oct;145(4):552-4. [Article]
- Thompson CA: Carglumic acid approved to treat genetic hyperammonemia. Am J Health Syst Pharm. 2010 May 1;67(9):690. doi: 10.2146/news100031. [Article]
- Haberle J: Role of carglumic acid in the treatment of acute hyperammonemia due to N-acetylglutamate synthase deficiency. Ther Clin Risk Manag. 2011;7:327-32. doi: 10.2147/TCRM.S12703. Epub 2011 Aug 2. [Article]
- Carbaglu [Link]
- FDA Approved Drug Products: CARBAGLU (carglumic acid) tablets for oral suspension [Link]
- External Links
- Human Metabolome Database
- HMDB0015673
- KEGG Drug
- D07130
- KEGG Compound
- C05829
- PubChem Compound
- 121396
- PubChem Substance
- 99443290
- ChemSpider
- 108351
- 401713
- ChEBI
- 71028
- ChEMBL
- CHEMBL1201780
- ZINC
- ZINC000001530283
- PharmGKB
- PA165958402
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Carglumic_acid
- FDA label
- Download (351 KB)
- MSDS
- Download (82.3 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Completed Treatment Methylmalonic Acidemia (MMA) / Propionic Acidemia (PA) 1 2 Completed Treatment Carbamoyl-Phosphate Synthase I Deficiency Disease / Methylmalonic Acidemia (MMA) / Ornithine Transcarbamylase Deficiency / Propionic Acidemia, Type I and/or Type II 1 2 Terminated Treatment Methylmalonic Acidemia (MMA) / Propionic Acidemia (PA) 1 2 Withdrawn Treatment Carbamyl Phosphate Synthetase Deficiency / Inborn Errors of Metabolism / Methylmalonic Acidemia (MMA) / Propionic Acidemia (PA) / Urea Cycle Disorders, Inborn 1 2, 3 Unknown Status Treatment Inborn Errors of Metabolism 1 Not Available Recruiting Not Available Hyperammonaemia / Methylmalonic Acidemia (MMA) / Propionic Acidemia (PA) 1 Not Available Recruiting Not Available Methylmalonic Acidemia (MMA) / Propionic Acidemia (PA) 1 Not Available Unknown Status Treatment Propionic Acidemia (PA) , Methylmalonic Acidemia (MMA) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, for suspension Oral 200 mg/1 Tablet, for suspension Oral 200 mg Tablet, soluble Oral 200 mg Tablet, orally disintegrating Oral 200 mg - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source logP -1.097 MSDS - Predicted Properties
Property Value Source Water Solubility 19.1 mg/mL ALOGPS logP -1.1 ALOGPS logP -1.4 Chemaxon logS -1 ALOGPS pKa (Strongest Acidic) 3.36 Chemaxon pKa (Strongest Basic) -2.3 Chemaxon Physiological Charge -2 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 4 Chemaxon Polar Surface Area 129.72 Å2 Chemaxon Rotatable Bond Count 5 Chemaxon Refractivity 39.41 m3·mol-1 Chemaxon Polarizability 16.79 Å3 Chemaxon Number of Rings 0 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption - 0.8269 Blood Brain Barrier + 0.9054 Caco-2 permeable - 0.8554 P-glycoprotein substrate Non-substrate 0.6682 P-glycoprotein inhibitor I Non-inhibitor 0.9775 P-glycoprotein inhibitor II Non-inhibitor 0.9945 Renal organic cation transporter Non-inhibitor 0.9589 CYP450 2C9 substrate Non-substrate 0.748 CYP450 2D6 substrate Non-substrate 0.8273 CYP450 3A4 substrate Non-substrate 0.7701 CYP450 1A2 substrate Non-inhibitor 0.9399 CYP450 2C9 inhibitor Non-inhibitor 0.9371 CYP450 2D6 inhibitor Non-inhibitor 0.955 CYP450 2C19 inhibitor Non-inhibitor 0.9447 CYP450 3A4 inhibitor Non-inhibitor 0.8408 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9909 Ames test Non AMES toxic 0.8509 Carcinogenicity Non-carcinogens 0.9372 Biodegradation Ready biodegradable 0.912 Rat acute toxicity 1.3576 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9741 hERG inhibition (predictor II) Non-inhibitor 0.9818
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Targets
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- 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
- CPS1
- Uniprot ID
- P31327
- Uniprot Name
- Carbamoyl-phosphate synthase [ammonia], mitochondrial
- Molecular Weight
- 164938.145 Da
References
- Authors unspecified: Carglumic acid: a second look. Confirmed progress in a rare urea cycle disorder. Prescrire Int. 2008 Apr;17(94):50-1. [Article]
- 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. [Article]
- 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. [Article]
Drug created at September 14, 2010 16:21 / Updated at October 06, 2022 03:22