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Identification
NameCarglumic Acid
Accession NumberDB06775
TypeSmall Molecule
GroupsApproved
DescriptionCarglumic 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.
Structure
Thumb
Synonyms
(2S)-2-(Carbamoylamino)pentanedioic acid
(S)-2-ureidopentanedioic acid
Acide carglumique
Acido carglumico
Acidum carglumicum
Carbaglu
Carbamino-L-glutamic acid
Carbamylglutamic acid
L-N-Carbamoylglutamic acid
N-Carbamoyl-L-Glutamic Acid
N-Carbamyl-L-glutamate
N-Carbamylglutamate
Ureidoglutaric acid
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
CarbagluTablet200 mg/1OralOrphan Europe, SARL2010-03-18Not applicableUs
CarbagluTablet, for suspension200 mgOralOrphan Europe S.A.R.L.2003-01-24Not applicableEu
CarbagluTablet, orally disintegrating200 mgOralOrphan Europe Sarl2015-09-08Not applicableCanada
CarbagluTablet, for suspension200 mgOralOrphan Europe S.A.R.L.2003-01-24Not applicableEu
CarbagluTablet, for suspension200 mgOralOrphan Europe S.A.R.L.2003-01-24Not applicableEu
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII5L0HB4V1EW
CAS number1188-38-1
WeightAverage: 190.154
Monoisotopic: 190.05897144
Chemical FormulaC6H10N2O5
InChI KeyLCQLHJZYVOQKHU-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
Pharmacology
IndicationFor 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.
Structured Indications
PharmacodynamicsThe 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 actionCarglumic 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.
TargetKindPharmacological actionActionsOrganismUniProt ID
Carbamoyl-phosphate synthase [ammonia], mitochondrialProteinyes
allosteric modulator
HumanP31327 details
Related Articles
Absorption30% 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 bindingNot 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 eliminationFollowing 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 lifeMedian 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).

ToxicityLD50, oral, mouse: >1000 mg/kg
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
Interactions
Drug InteractionsNo interactions found.
Food InteractionsNot Available
References
Synthesis ReferenceNot Available
General References
  1. 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. [PubMed:12447942 ]
  2. 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. [PubMed:15480384 ]
  3. Thompson CA: Carglumic acid approved to treat genetic hyperammonemia. Am J Health Syst Pharm. 2010 May 1;67(9):690. doi: 10.2146/news100031. [PubMed:20410539 ]
  4. 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. [PubMed:21941437 ]
  5. Carbaglu [Link]
External Links
ATC CodesA16AA05
AHFS Codes
  • 40:10
PDB EntriesNot Available
FDA labelDownload (351 KB)
MSDSDownload (82.3 KB)
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.8269
Blood Brain Barrier+0.9054
Caco-2 permeable-0.8554
P-glycoprotein substrateNon-substrate0.6682
P-glycoprotein inhibitor INon-inhibitor0.9775
P-glycoprotein inhibitor IINon-inhibitor0.9945
Renal organic cation transporterNon-inhibitor0.9589
CYP450 2C9 substrateNon-substrate0.748
CYP450 2D6 substrateNon-substrate0.8273
CYP450 3A4 substrateNon-substrate0.7701
CYP450 1A2 substrateNon-inhibitor0.9399
CYP450 2C9 inhibitorNon-inhibitor0.9371
CYP450 2D6 inhibitorNon-inhibitor0.955
CYP450 2C19 inhibitorNon-inhibitor0.9447
CYP450 3A4 inhibitorNon-inhibitor0.8408
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9909
Ames testNon AMES toxic0.8509
CarcinogenicityNon-carcinogens0.9372
BiodegradationReady biodegradable0.912
Rat acute toxicity1.3576 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9741
hERG inhibition (predictor II)Non-inhibitor0.9818
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
TabletOral200 mg/1
Tablet, for suspensionOral200 mg
Tablet, orally disintegratingOral200 mg
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
logP-1.097MSDS
Predicted Properties
PropertyValueSource
Water Solubility19.1 mg/mLALOGPS
logP-1.1ALOGPS
logP-1.4ChemAxon
logS-1ALOGPS
pKa (Strongest Acidic)3.36ChemAxon
pKa (Strongest Basic)-2.3ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area129.72 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity39.41 m3·mol-1ChemAxon
Polarizability16.78 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as n-carbamoyl-alpha amino acids. These are compounds containing an alpha amino acid which bears an carbamoyl group at its terminal nitrogen atom.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentN-carbamoyl-alpha amino acids
Alternative Parents
Substituents
  • N-carbamoyl-alpha-amino acid
  • Amino fatty acid
  • Fatty acyl
  • Fatty acid
  • Dicarboxylic acid or derivatives
  • Urea
  • Carboxylic acid
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Aliphatic acyclic compound
Molecular FrameworkAliphatic acyclic compounds
External Descriptors

Targets

Kind
Protein
Organism
Human
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
Molecular Weight:
164938.145 Da
References
  1. 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 ]
  2. 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 ]
  3. 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 ]
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Drug created on September 14, 2010 10:21 / Updated on August 17, 2016 12:24