In a dose-dependent way, carglumic acid decreases the cell viability of human non-small cell lung cancer, triple-negative breast cancer, pancreatic ductal adenocarcinoma, and liver cancer cell lines. For these cell lines, the range of carglumic acid's 50% inhibitory concentration (IC50) is 5 to 7.5 mM. The findings show that kagaric acid does not cause a total stoppage of the cell cycle. AsPC1 and MDA-MB-231 cells treated with karglulic acid, on the other hand, had a higher number of sub-G1 cells than untreated cells. In AsPC1 and HPDE-E6E7 cells, the IC50 of carbamic acid was 5 mM and more than 10 mM, respectively. The IC50 of carboxylic acid is 5 mM in MDA-MB-231 and 6 mM in MCF-12A cells, respectively[1].

The findings demonstrated that karglulic acid markedly slowed tumor growth, but not the vehicle control. On day 21, karglulic acid's tumor growth-inhibiting rate in the orthotopic pancreatic cancer model was 80% (P<0.01). On day 20, 82% (P<0.01) of the orthotopic triple-negative breast cancer model's tumor development was inhibited by karglulic acid. These findings suggest that karglulic acid suppresses triple-negative breast cancer and pancreatic cancer tumor growth. On day 20, animals receiving oral and intravenous treatment had average tumor growth inhibition rates of 55% and 93%, respectively (P<0.01) [1].

Absorption, Distribution and Excretion
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.
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.
The apparent volume of distribution was 2657 L (range: 1616-5797).
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).

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Metabolism / Metabolites
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.

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Biological Half-Life
Median values for the terminal half-life was 5.6 hours (range 4.3-9.5).

[1]. Carglumic acid promotes apoptosis and suppresses cancer cell proliferation in vitro and in vivo. Am J Cancer Res. 2015 Nov 15;5(12):3560-9.

Carglumic acid is a urea that is the N-carbamoyl derivative of L-glutamic acid. An orphan drug used to treat a deficiency in the enzyme N-acetylglutamate synthase, which leads to acute hyperammonaemia. It has a role as an orphan drug and a carbamylphosphate synthetase I activator. It is a N-acyl-L-glutamic acid and a member of ureas. It is a conjugate acid of a N-carbamoyl-L-glutamate(2-).
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.
Carglumic acid is a Carbamoyl Phosphate Synthetase 1 Activator. The mechanism of action of carglumic acid is as a Carbamoyl Phosphate Synthetase 1 Activator.
Carglumic acid has been reported in Caenorhabditis elegans with data available.
Carglumic Acid is an orally active, synthetic structural analogue of N-acetylglutamate (NAG) and carbamoyl phosphate synthetase 1 (CPS 1) activator, with ammonia lowering activity. NAG, which is formed by the hepatic enzyme N-acetylglutamate synthase (NAGS), is an essential allosteric activator of the enzyme carbamoyl phosphate synthetase 1 (CPS 1). CPS 1 plays an essential role in the urea cycle and converts ammonia into urea. Upon oral administration, carglumic acid can replace NAG in NAGS deficient patients and activates CPS 1, which prevents hyperammonaemia.

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Drug 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.
FDA Label
Carbaglu is indicated in treatment of: hyperammonaemia due to N-acetylglutamate-synthase primary deficiency; hyperammonaemia due to isovaleric acidaemia; hyperammonaemia due to methymalonic acidaemia; hyperammonaemia due to propionic acidaemia.
Ucedane is indicated in treatment of: hyperammonaemia due to N-acetylglutamate synthase primary deficiency; Hyperammonaemia due to isovaleric acidaemia; Hyperammonaemia due to methymalonic acidaemia; Hyperammonaemia due to propionic acidaemia.

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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.

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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.

C6H10N2O5

190.154

190.059

1188-38-1

121396

White to off-white solid powder

1.499g/cm3

438.1ºC at 760 mmHg

174°

218.8ºC

6.7E-09mmHg at 25°C

1.544

0.063

4

5

5

13

227

1

C(CC(=O)O)[C@@H](C(=O)O)NC(=O)N

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

(2S)-2-(carbamoylamino)pentanedioic acid

Carglumic Acid; OE312, OE-312, OE 312, AJ 266447, AJ-26647, AJ26647

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~525.90 mM)
H2O : ~10 mg/mL (~52.59 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (13.15 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (13.15 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (13.15 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 37.5 mg/mL (197.21 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)