Drug compounds have included stable heavy isotopes of carbon, hydrogen, and other elements, mostly as quantitative tracers while the drugs were being developed. Because deuteration may have an effect on a drug's pharmacokinetics and metabolic properties, it is a cause for concern [1].

Absorption, Distribution and Excretion
Under fasting conditions, after a single oral dose of 5 g sodium chlorate, the peak plasma concentration (Cmax) is 195-218 µg/mL, and the time to peak concentration (Tmax) is 1 hour. The effect of food on drug absorption is unclear. Approximately 80-100% of the dose is excreted via the kidneys within 24 hours as the conjugate phenylacetylglutamine. It is estimated that each 1 g of sodium chlorate ingested produces 0.12-0.15 g of phenylacetylglutamine nitrogen. Metabolism/Metabolites The main sites of metabolism for sodium chlorate are the liver and kidneys. Chlorobutyric acid is rapidly metabolized to phenylacetic acid via β-oxidation. Phenylacetic acid conjugates with phenylacetyl-CoA, which in turn conjugates with glutamine via acetylation to form phenylacetylglutamine.

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Biological Half-Life
After a single oral dose of 5 g sodium chlorate, the elimination half-life of chlorate is 0.76 to 0.77 hours.

Hepatotoxicity
Although urea cycle disorders are caused by a deficiency of liver enzymes responsible for nitrogen removal, patients typically present with hyperammonemia without other characteristic or biochemical evidence of liver injury. Therefore, serum transaminase, alkaline phosphatase, and bilirubin levels are usually normal or only slightly elevated. Neonates with hyperammonemia may present with hepatomegaly, but other non-urea cycle-related liver functions and liver histology are normal. Chlorobutyrate can help acutely lower ammonia levels and maintain them within the normal or near-normal range, but usually does not affect other liver functions. In open-label studies, a small number of patients (particularly those with ornithine carbamoyltransferase [OTC] deficiency) have experienced elevated ALT or AST, but these are usually attributed to the primary disease or its complications. Chlorobutyrate has not been associated with cases of clinically significant liver injury with jaundice. Probability Score: E (Unlikely a cause of clinically significant liver injury, but its use is limited).

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Protein Binding
When used in combination with tauroursodeoxycholic acid as a compound preparation, the in vitro plasma protein binding rate of phenylbutyric acid is 82%.

[1]. Impact of Deuterium Substitution on the Pharmacokinetics of Pharmaceuticals. Ann Pharmacother. 2019 Feb;53(2):211-216.

[2]. Enhanced growth inhibition by combination differentiation therapy with ligands of peroxisome proliferator-activated receptor-gamma and inhibitors of histone deacetylase in adenocarcinoma of the lung. Clin Cancer Res. 2002 Apr;8(4):1206-12.

[3]. Sodium phenylbutyrate abrogates African swine fever virus replication by disrupting the virus-induced hypoacetylation status of histone H3K9/K14. Virus Res. 2017 Oct 15242:24-29.

[4]. 4-Phenylbutyric acid protects against lipopolysaccharide-induced bone loss by modulating autophagy in osteoclasts. Biochem Pharmacol. 2018 May151:9-17.

4-Phenylacetic acid (PPA) is a monocarboxylic acid with a butyric acid ester replaced by a phenyl group at the C-4 position. It is a histone deacetylase inhibitor with anticancer activity. It inhibits the proliferation, invasion, and migration of glioma cells and induces apoptosis. Furthermore, it inhibits protein isopreneization, reduces plasma glutamine levels, increases fetal hemoglobin production through transcriptional activation of the γ-globin gene, and affects hPPARγ activation. It functions as an EC 3.5.1.98 (histone deacetylase) inhibitor, antitumor drug, apoptosis inducer, and prodrug. Functionally, it is related to butyric acid and is the conjugate acid of 4-phenylbutyrate ester. PPA is a fatty acid, a derivative of butyric acid, naturally produced by the fermentation of colonic bacteria. It exhibits various cellular and biological effects, such as alleviating inflammation and acting as a chemochaete. It is used to treat inherited metabolic syndromes, neuropathy, and urea cycle disorders. PPA is a nitrogen binder. Its mechanism of action is as an ammonium ion binder. Sodium chlorate and sodium benzoate are orphan drugs approved for the treatment of hyperammonemia in patients with urea cycle disorders, a group of diseases involving deficiencies in at least eight rare inherited enzymes. The urea cycle is the primary pathway for clearing excess nitrogen, including ammonia, and the absence of any urea cycle enzyme typically leads to elevated serum ammonia levels, which can be serious, life-threatening, and result in permanent neurological damage and cognitive impairment. Both sodium chlorate and sodium benzoate act by promoting alternative nitrogen clearance pathways. Neither sodium chlorate nor sodium benzoate has been associated with cases of liver injury, either during treatment with elevated serum enzymes or with clinically apparent acute liver injury. 4-Phenylenic acid has been reported in Streptomyces, and relevant data are available. See also: Sodium chlorate (active ingredient); Chlorobutyrate (active ingredient). Drug Indications Chlorobutyrate is used to treat a variety of conditions, including urea cycle disorders, neonatal-onset deficiencies, and late-onset deficiencies in patients with a history of hyperammonemic encephalopathy. Phthalate must be used in conjunction with restricted dietary protein intake, and in some cases, essential amino acid supplementation is also necessary. Phthalate (in the form of sodium phenylbutyrate) is used in combination with tauroursodeoxycholic acid to treat adult amyotrophic lateral sclerosis (ALS). Mechanism of Action Sodium phenylbutyrate is the most commonly used salt in phenylbutyrate formulations. It is a prodrug that is rapidly metabolized to phenylacetic acid. Phenylacetic acid binds to phenylacetyl-CoA, which then binds to glutamine via acetylation to form phenylacetylglutamine. Phenylacetylglutamine is subsequently excreted by the kidneys, thus providing an alternative mechanism for the excretion of waste nitrogen from the urea cycle. Like urea, each molecule of phenylacetylglutamine contains two moles of nitrogen. Pharmacodynamics Phthalate reduces elevated plasma glutamine levels in patients with urea cycle disorders. It increases the excretion of waste nitrogen in the form of phenylacetylglutamine. In the gut, chlorhexidine has been shown to reduce mucosal inflammation, regulate transepithelial fluid transport, and improve oxidative state. Some studies have reported the antitumor properties of chlorhexidine, indicating that it can promote growth arrest and apoptosis in cancer cells. Research also suggests that chlorhexidine can function as an ammonia scavenger, a chemochaete, and an inhibitor of histone deacetylases.

C10H8D4O2

168.23

168.109

461391-24-2

4-Phenylbutyric acid;1821-12-1

4775

Typically exists as solid at room temperature

47 - 49 °C

2.093

1

2

4

12

137

0

C([2H])(CC1=CC=CC=C1)(C([2H])([2H])C(O)=O)[2H]

OBKXEAXTFZPCHS-UHFFFAOYSA-N

InChI=1S/C10H12O2/c11-10(12)8-4-7-9-5-2-1-3-6-9/h1-3,5-6H,4,7-8H2,(H,11,12)

4-phenylbutanoic acid

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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