Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C6H10N2O5 |
Molecular Weight | 190.154 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 1 / 1 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
NC(=O)N[C@@H](CCC(O)=O)C(O)=O
InChI
InChIKey=LCQLHJZYVOQKHU-VKHMYHEASA-N
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
Molecular Formula | C6H10N2O5 |
Molecular Weight | 190.154 |
Charge | 0 |
Count |
|
Stereochemistry | ABSOLUTE |
Additional Stereochemistry | No |
Defined Stereocenters | 1 / 1 |
E/Z Centers | 0 |
Optical Activity | UNSPECIFIED |
Carglumic acid is a Carbamoyl Phosphate Synthetase 1 (CPS 1) allosteric modulator. 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. Carglumic acid under the trade name Carbaglu indicated as adjunctive therapy for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). In addition, as maintenance therapy for the treatment of chronic hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). 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.
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
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Target ID: CHEMBL2362990 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21403788 |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | CARBAGLU Approved UseCarbaglu (carglumic acid) is a Carbamoyl Phosphate Synthetase 1 (CPS 1) activator indicated as:
• Adjunctive therapy for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). (1.1)
• Maintenance therapy for the treatment of chronic hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). (1.2) Launch Date2010 |
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Palliative | CARBAGLU Approved UseCarbaglu (carglumic acid) is a Carbamoyl Phosphate Synthetase 1 (CPS 1) activator indicated as:
• Adjunctive therapy for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). (1.1)
• Maintenance therapy for the treatment of chronic hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). (1.2) Launch Date2010 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
2892 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25677217/ |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
CARGLUMIC ACID plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
2.6 μg/mL |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
CARGLUMIC ACID plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
23.2 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25677217/ |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
CARGLUMIC ACID plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
5.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25677217/ |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
CARGLUMIC ACID plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
5.6 h |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
CARGLUMIC ACID plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
---|---|---|
96.3 mg/kg 2 times / day multiple, oral Recommended Dose: 96.3 mg/kg, 2 times / day Route: oral Route: multiple Dose: 96.3 mg/kg, 2 times / day Sources: |
unhealthy, 5 day n = 21 Health Status: unhealthy Condition: methylmalonic aciduria Age Group: 5 day Sex: M+F Population Size: 21 Sources: |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
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Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 11-12, 38 |
no | |||
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42 |
no | |||
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42 |
no | |||
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 11-12, 38 |
no | |||
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42 |
no | |||
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42 |
no | |||
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42 |
no | |||
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42 |
no | |||
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42 |
no | |||
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42 |
no | |||
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 11-12, 38 |
no | |||
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42 |
no |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 30, 35 |
no | |||
Page: 30.0 |
no | |||
Page: 30.0 |
no | |||
Page: 30.0 |
no |
PubMed
Title | Date | PubMed |
---|---|---|
[Orphan drugs and metabolic disorders]. | 2001 Aug 1-15 |
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Mixture of N-carbamoyl-L-glutamate plus L-arginine can protect rats with liver cirrhosis from acute ammonia intoxication. | 2001 Dec |
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Hyperinsulinism and hyperammonemia syndrome: report of twelve unrelated patients. | 2001 Sep |
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N-acetylglutamate synthase deficiency and the treatment of hyperammonemic encephalopathy. | 2002 Dec |
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N-carbamylglutamate enhances ammonia detoxification in a patient with decompensated methylmalonic aciduria. | 2003 Aug |
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Hyperammonaemia as a cause of psychosis in an adolescent. | 2003 Nov |
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Mammalian N-acetylglutamate synthase. | 2004 Apr |
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Carglumic acid: new preparation. An advance in rare urea cycle disorders. | 2004 Feb |
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Urea synthesis by ruminal epithelial and duodenal mucosal cells from growing sheep. | 2004 Jun |
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Restoration of ureagenesis in N-acetylglutamate synthase deficiency by N-carbamylglutamate. | 2004 Oct |
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N-carbamylglutamate protects patients with decompensated propionic aciduria from hyperammonaemia. | 2005 |
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Neonatal hyperammonemia: the N-carbamoyl-L-glutamic acid test. | 2005 Aug |
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Misleading diagnosis of partial N-acetylglutamate synthase deficiency based on enzyme measurement corrected by mutation analysis. | 2005 Jan |
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Metabolic fates of ammonia-N in ruminal epithelial and duodenal mucosal cells isolated from growing sheep. | 2005 Nov |
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Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene. | 2007 Aug |
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A trial with N-carbamylglutamate may not detect all patients with NAGS deficiency and neonatal onset. | 2007 Jun |
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Carglumic acid: a second look. Confirmed progress in a rare urea cycle disorder. | 2008 Apr |
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N-carbamylglutamate markedly enhances ureagenesis in N-acetylglutamate deficiency and propionic acidemia as measured by isotopic incorporation and blood biomarkers. | 2008 Aug |
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N-carbamylglutamate for neonatal hyperammonaemia in propionic acidaemia. | 2008 Dec |
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Carglumic acid: an additional therapy in the treatment of organic acidurias with hyperammonemia? | 2008 Jan 30 |
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[A newborn infant with hyperventilation]. | 2008 Jun 26 |
|
Uncovering metabolic pathways relevant to phenotypic traits of microbial genomes. | 2009 |
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[N-carbamyl glutamate treatment in hyperammoniemia decompensated propionic acidaemia]. | 2009 Dec |
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Effects of a single dose of N-carbamylglutamate on the rate of ureagenesis. | 2009 Dec |
|
Pricing of orphan drugs. | 2009 Feb 7 |
|
The first use of N-carbamylglutamate in a patient with decompensated maple syrup urine disease. | 2009 Sep |
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N-acetylglutamate synthase: structure, function and defects. | 2010 |
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N-carbamylglutamate in emergency management of hyperammonemia in neonatal acute onset propionic and methylmalonic aciduria. | 2010 |
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Outpatient treatment of propionic acidemia-associated hyperammonemia with N-carbamoyl-L-glutamate in an infant. | 2010 Apr |
|
Dietary supplementation with L-arginine or N-carbamylglutamate enhances intestinal growth and heat shock protein-70 expression in weanling pigs fed a corn- and soybean meal-based diet. | 2010 Aug |
|
Gateways to clinical trials. | 2010 Dec |
|
Favourable long-term outcome after immediate treatment of neonatal hyperammonemia due to N-acetylglutamate synthase deficiency. | 2010 Feb |
|
Biochemical efficacy of N-carbamylglutamate in neonatal severe hyperammonaemia due to propionic acidaemia. | 2010 Jan |
|
N-carbamylglutamate augments ureagenesis and reduces ammonia and glutamine in propionic acidemia. | 2010 Jul |
|
Role of carglumic acid in the treatment of acute hyperammonemia due to N-acetylglutamate synthase deficiency. | 2011 |
Sample Use Guides
Adult Dosage: The recommended initial dose for acute hyperammonemia is 100 mg/kg/day to 250 mg/kg/day. Concomitant administration of other ammonia lowering therapies is recommended. Dosing should be titrated based on individual patient plasma ammonia levels and clinical symptoms.
The recommended maintenance dose should be titrated to target normal plasma ammonia level for age. Based on limited data in 22 patients receiving maintenance treatment with Carbaglu in a retrospective case series, maintenance doses were usually less than 100 mg/kg/day. The total daily dose should be divided into 2 to 4 doses and rounded to the nearest 100 mg. (i.e. half a Carbaglu Tablet)
Pediatric Dosage: The recommended initial dose for acute hyperammonemia is 100 mg/kg/day to 250 mg/kg/day. Concomitant administration of other ammonia lowering therapies is recommended. Dosing should be titrated based on individual patient plasma ammonia levels and clinical symptoms. The recommended maintenance dose should be titrated to target normal plasma ammonia level for age. Based on limited data in 22 patients receiving maintenance treatment with Carbaglu in a retrospective case series, maintenance doses were usually less than 100 mg/kg/day. The total daily dose should be divided into 2 to 4 doses.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26885446
Carglumic acid-treated (1, 5, 10 mM) and untreated cancer cells were stained with propidium iodide to determine DNA contents in the human pancreatic adenocarcinoma cell lines, AsPC1 and human triple-negative breast cancer cell lines MDA-MB-231. The results showed that carglumic acid did not induce complete cell cycle arrest. Instead, we observed more sub-G1 cells among carglumic acid-treated AsPC1 and MDA-MB-231 cells than among untreated cells, indicating that cell death occurred in response to carglumic acid. Sub-G1 cells accounted for 1.6% and 26.3% of untreated and treated AsPC1 cells, respectively , and for 1.8% and 12.8% of untreated and treated MDA-MB-231 cells, respectively. In order to further determine whether cancer cells under go cell death through apoptosis after carglumic acid treatment, we measured caspase activity in AsPC1 cells treated with carglumic acid. The results showed that caspase-3 activity increased in a dose-dependent manner. Together, these data suggest that carglumic acid inhibits cancer cell proliferation by inducing apoptosis.
Substance Class |
Chemical
Created
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on
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Record UNII |
5L0HB4V1EW
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Record Status |
Validated (UNII)
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Record Version |
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Classification Tree | Code System | Code | ||
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EMA ASSESSMENT REPORTS |
CARBAGLU (AUTHORIZED: AMINO ACID METABOLISM, INBORN ERRORS)
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FDA ORPHAN DRUG |
109997
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WHO-VATC |
QA16AA05
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EU-Orphan Drug |
EU/3/00/007
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NDF-RT |
N0000184144
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WHO-ATC |
A16AA05
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NCI_THESAURUS |
C78275
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FDA ORPHAN DRUG |
352111
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m3108
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100000089544
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1096586
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1188-38-1
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SUB20051
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CARGLUMIC ACID
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C76884
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401713
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121396
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CHEMBL1201780
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N0000184143
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71028
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DB06775
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SUB13236MIG
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ALTERNATIVE |
Related Record | Type | Details | ||
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TARGET -> ACTIVATOR | |||
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EXCRETED UNCHANGED |
Following administration of a single radiolabeled oral dose of 100 mg/kg of body weight up to 60% of the dose was excreted unchanged in the feces.
FECAL
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EXCRETED UNCHANGED |
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.
URINE
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Related Record | Type | Details | ||
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IMPURITY -> PARENT |
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Related Record | Type | Details | ||
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ACTIVE MOIETY |
Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
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Biological Half-life | PHARMACOKINETIC |
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Tmax | PHARMACOKINETIC |
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Volume of Distribution | PHARMACOKINETIC |
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