Identification
- Summary
Phenylbutyric acid is an agent indicated for the adjunctive therapy for the management of chronic urea cycle disorders due to deficiencies in specific enzymes, including the neonatal-onset deficiency and late-onset disease with a history of hyperammonemic encephalopathy.
- Brand Names
- Ammonaps, Buphenyl, Pheburane
- Generic Name
- Phenylbutyric acid
- DrugBank Accession Number
- DB06819
- Background
Phenylbutyric acid is a fatty acid and a derivative of butyric acid naturally produced by colonic bacteria fermentation. It demonstrates a number of cellular and biological effects, such as relieving inflammation and acting as a chemical chaperone.1 It is used to treat genetic metabolic syndromes, neuropathies, and urea cycle disorders.2,3
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Phenylbutyric acid (DB06819)
- Weight
- Average: 164.2011
Monoisotopic: 164.083729628 - Chemical Formula
- C10H12O2
- Synonyms
- 4-Phenyl-n-butyric acid
- 4-phenylbutyrate
- 4-phenylbutyric acid
- Benzenebutyric acid
- PBA
- Phenylbutyrate
- γ-Phenyl-n-butyric acid
- γ-phenylbutyric acid
- ω-Phenylbutanoic acid
- ω-phenylbutyric acid
- External IDs
- NSC-295
Pharmacology
- Indication
Phenylbutyric acid is used for the treatment of various conditions, including urea cycle disorders, neonatal-onset deficiency, late-onset deficiency disease in patients with a history of hyperammonemic encephalopathy. Phenylbutyric acid must be combined with dietary protein restriction and, in some cases, essential amino acid supplementation.2
Phenylbutyric acid, as sodium phenylbutyrate, is used in combination with tauroursodeoxycholic acid to treat amyotrophic lateral sclerosis (ALS) in adults.3
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- Contraindications & Blackbox Warnings
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Phenylbutyric acid decreases elevated plasma ammonia glutamine levels in patients with urea cycle disorders. It increases waste nitrogen excretion in the form of phenylacetylglutamine.2
In the intestines, phenylbutyric acid was shown to reduce mucosal inflammation, regulate transepithelial fluid transport, and improve oxidative status. Some studies report antineoplastic properties of phenylbutyric acid, showing that phenylbutyric acid can promote growth arrest and apoptosis of cancer cells. It is suggested that phenylbutyric acid can act as an ammonia scavenger, chemical chaperone, and histone deacetylase inhibitor.1
- Mechanism of action
Sodium phenylbutyrate is the most commonly used salt used in drug products of phenylbutyric acid. Sodium phenylbutyrate is a pro-drug that rapidly metabolizes to phenylacetate.2 Phenylacetate is conjugated with phenylacetyl-CoA, which in turn combines with glutamine via acetylation to form phenylacetylglutamine. Phenylacetylglutamine is then excreted by the kidneys, thus providing an alternate mechanism of waste nitrogen excretion to the urea cycle.4 Phenylacetylglutamine is comparable to urea, as each molecule contains two moles of nitrogen.2
Target Actions Organism UAromatic-amino-acid aminotransferase Not Available Paracoccus denitrificans UHistone deacetylase inhibitorHumans - Absorption
Following oral administration of a single 5g dose of sodium phenylbutyrate, the Cmax was 195-218 µg/mL under fasting conditions and the Tmax was one hour. The effect of food on drug absorption is unknown.2
- Volume of distribution
Not Available
- Protein binding
When co-administered with tauroursodeoxycholic acid as a combination product, the in vitro plasma protein binding of phenylbutyric acid is 82%.3
- Metabolism
The major sites for metabolism of sodium phenylbutyrate are the liver and kidney.2 Phenylbutyric acid is rapidly metabolized to phenylacetate via beta-oxidation. Phenylacetate is conjugated with phenylacetyl-CoA, which in turn combines with glutamine via acetylation to form phenylacetylglutamine.4
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- Route of elimination
Approximately 80–100% of the dose was excreted by the kidneys within 24 hours as the conjugation product, phenylacetylglutamine. For each gram of sodium phenylbutyrate administered, it is estimated that between 0.12–0.15 grams of phenylacetylglutamine nitrogen are produced.2
- Half-life
Following oral administration of a single 5g dose of sodium phenylbutyrate, the elimination half-life of phenylbutyric acid ranged from 0.76 to 0.77 hours.2
- Clearance
Not Available
- Adverse Effects
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In animals, lethality was seen at a dose of 1586 mg/kg sodium phenylbutyrate; however, this is a supra-therapeutic dose and acute toxicity is unlikely.4 No adverse experiences have been reported involving overdoses of sodium phenylbutyrate in patients with urea cycle disorders. High levels of phenylacetate, the active metabolite of phenylbutyric acid, can cause nausea, headache, emesis, fatigue, weakness, lethargy, somnolence, dizziness, slurred speech, memory loss, confusion, and disorientation.3
In the event of an overdose, discontinue the drug and institute supportive measures. Hemodialysis or peritoneal dialysis may be beneficial.2 Animal studies in the scientific literature have demonstrated the embryo-fetal toxicity potential of phenylacetate, the major metabolite of phenylbutyrate.3
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAcebutolol The metabolism of Acebutolol can be decreased when combined with Phenylbutyric acid. Acetaminophen The metabolism of Acetaminophen can be decreased when combined with Phenylbutyric acid. Almotriptan The metabolism of Almotriptan can be decreased when combined with Phenylbutyric acid. Alogliptin The metabolism of Alogliptin can be decreased when combined with Phenylbutyric acid. Aminophenazone The metabolism of Aminophenazone can be decreased when combined with Phenylbutyric acid. Amitriptyline The metabolism of Amitriptyline can be decreased when combined with Phenylbutyric acid. Amoxapine The metabolism of Amoxapine can be decreased when combined with Phenylbutyric acid. Amphetamine The metabolism of Amphetamine can be decreased when combined with Phenylbutyric acid. Amprenavir The metabolism of Amprenavir can be decreased when combined with Phenylbutyric acid. Antipyrine The metabolism of Antipyrine can be decreased when combined with Phenylbutyric acid. 
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- Take with food. The effect of food on phenylbutyrate’s absorption is unknown.
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.- Product Ingredients
Ingredient UNII CAS InChI Key Sodium phenylbutyrate NT6K61736T 1716-12-7 VPZRWNZGLKXFOE-UHFFFAOYSA-M - Product Images
- International/Other Brands
- triButyrate (Fyrlklövern Scandinavia)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Ammonaps Tablet 500 mg Oral Immedica Pharma Ab 2016-09-07 Not applicable EU 
Ammonaps Granule 940 mg/g Oral Immedica Pharma Ab 2016-09-07 Not applicable EU Ammonaps Tablet 500 mg Oral Immedica Pharma Ab 2016-09-07 Not applicable EU Ammonaps Granule 940 mg/g Oral Immedica Pharma Ab 2016-09-07 Not applicable EU Buphenyl Tablet 500 mg/1 Oral Ucyclyd Pharma Inc. 1996-05-13 2015-02-28 US 
Buphenyl Powder 0.94 g/1g Oral Horizon Therapeutics USA, Inc. 1996-04-30 Not applicable US Buphenyl Tablet 500 mg/1 Oral Hyperion Therapeutics, Inc. 1996-05-13 2016-11-29 US Buphenyl Tablet 500 mg/1 Oral Horizon Therapeutics USA, Inc. 1996-05-13 Not applicable US Buphenyl Powder 0.94 g/1g Oral Ucyclyd Pharma Inc. 1996-04-30 2015-02-28 US Buphenyl Powder 0.94 g/1g Oral Hyperion Therapeutics, Inc. 1996-04-30 2016-11-29 US - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Sodium Phenylbutyrate Powder 0.94 g/1g Oral Par Pharmaceutical 2016-08-31 Not applicable US 
Sodium Phenylbutyrate Tablet 500 mg/1 Oral Par Pharmaceutical, Inc. 2016-04-29 Not applicable US Sodium Phenylbutyrate Powder 0.94 g/1g Oral Sigmapharm Laboratories, LLC 2013-04-08 Not applicable US Sodium Phenylbutyrate Tablet 500 mg/1 Oral Mikart, LLC 2011-11-18 2011-11-19 US
Categories
- ATC Codes
- A16AX03 — Sodium phenylbutyrate
- Drug Categories
- Acids, Carbocyclic
- Alimentary Tract and Metabolism
- Ammonium Ion Binding Activity
- Antineoplastic Agents
- Cytochrome P-450 CYP2D6 Inhibitors
- Cytochrome P-450 CYP2D6 Inhibitors (moderate)
- Cytochrome P-450 Enzyme Inhibitors
- Nitrogen Binding Agent
- Urea Cycle Disorder Agents
- Various Alimentary Tract and Metabolism Products
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as benzene and substituted derivatives. These are aromatic compounds containing one monocyclic ring system consisting of benzene.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Not Available
- Direct Parent
- Benzene and substituted derivatives
- Alternative Parents
- Monocarboxylic acids and derivatives / Carboxylic acids / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
- Substituents
- Aromatic homomonocyclic compound / Carbonyl group / Carboxylic acid / Carboxylic acid derivative / Hydrocarbon derivative / Monocarboxylic acid or derivatives / Monocyclic benzene moiety / Organic oxide / Organic oxygen compound / Organooxygen compound
- Molecular Framework
- Aromatic homomonocyclic compounds
- External Descriptors
- monocarboxylic acid (CHEBI:41500)
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 7WY7YBI87E
- CAS number
- 1821-12-1
- InChI Key
- OBKXEAXTFZPCHS-UHFFFAOYSA-N
- InChI
- 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)
- IUPAC Name
- 4-phenylbutanoic acid
- SMILES
- OC(=O)CCCC1=CC=CC=C1
References
- General References
- Kusaczuk M, Bartoszewicz M, Cechowska-Pasko M: Phenylbutyric Acid: simple structure - multiple effects. Curr Pharm Des. 2015;21(16):2147-66. doi: 10.2174/1381612821666150105160059. [Article]
- FDA Approved Drug Products: BUPHENYL (sodium phenylbutyrate) Tablets or Powder, for oral administration [Link]
- Health Canada Approved Drug Products: ALBRIOZA (sodium phenylbutyrate and ursodoxicoltaurine) Oral Powder for suspension [Link]
- EMA Assessment Report: Pheburane (sodium phenylbutyrate) [Link]
- External Links
- Human Metabolome Database
- HMDB0000543
- KEGG Drug
- D05868
- PubChem Compound
- 4775
- PubChem Substance
- 310264895
- ChemSpider
- 4611
- BindingDB
- 50480960
- 1546447
- ChEBI
- 41500
- ChEMBL
- CHEMBL1469
- ZINC
- ZINC000000056568
- PDBe Ligand
- CLT
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Sodium_phenylbutyrate
- PDB Entries
- 2ay7 / 3tz2 / 3tz5 / 5vnl / 5vnm / 5vnn / 5yoq
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Completed Health Services Research Diabetes / Resistance, Insulin 1 4 Recruiting Treatment Deficiencies in enzymes of the urea cycle 1 3 Completed Treatment Deficiencies in enzymes of the urea cycle 1 2 Completed Treatment Alzheimer's Disease (AD) 1 2 Completed Treatment Amino Acid Metabolism, Inborn Errors 1 2 Completed Treatment Amino Acid Metabolism, Inborn Errors / Argininosuccinic Aciduria / Deficiencies in enzymes of the urea cycle 1 2 Completed Treatment Amyotrophic Lateral Sclerosis (ALS) / Central Nervous System Disorder / Motor Neurone Disease / Nervous System Diseases / Neurodegenerative Disorders / Neuromuscular Diseases / Spinal Cord Diseases / TDP-43 Proteinopathies 1 2 Completed Treatment Deficiencies in enzymes of the urea cycle 1 2 Completed Treatment Human Immunodeficiency Virus (HIV) Infections 1 2 Completed Treatment Huntington's Disease (HD) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Granule Oral 940 MG/G Tablet Oral 500 MG Powder Oral 0.94 g/1g Tablet Oral 500 mg/1 Granule Not applicable 869.6 g/1kg Granule Oral 483 MG/G Granule Oral 483 mg / g Granule Oral 48.3 g - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.513 mg/mL ALOGPS logP 2.29 ALOGPS logP 2.5 ChemAxon logS -2.5 ALOGPS pKa (Strongest Acidic) 4.81 ChemAxon Physiological Charge -1 ChemAxon Hydrogen Acceptor Count 2 ChemAxon Hydrogen Donor Count 1 ChemAxon Polar Surface Area 37.3 Å2 ChemAxon Rotatable Bond Count 4 ChemAxon Refractivity 46.57 m3·mol-1 ChemAxon Polarizability 17.99 Å3 ChemAxon Number of Rings 1 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter Yes ChemAxon Veber's Rule Yes ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Targets
- Kind
- Protein
- Organism
- Paracoccus denitrificans
- Pharmacological action
- Unknown
- General Function
- Pyridoxal phosphate binding
- Specific Function
- Shows activities toward both dicarboxylic and aromatic substrates.
- Gene Name
- tyrB
- Uniprot ID
- P95468
- Uniprot Name
- Aromatic-amino-acid aminotransferase
- Molecular Weight
- 42731.635 Da
References
- Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
- Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [Article]
- Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [Article]
- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Transcription regulatory region sequence-specific dna binding
- Specific Function
- Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an impo...
Components:
References
- Kouraklis G, Theocharis S: Histone deacetylase inhibitors: a novel target of anticancer therapy (review). Oncol Rep. 2006 Feb;15(2):489-94. [Article]
- Kouraklis G, Theocharis S: Histone deacetylase inhibitors and anticancer therapy. Curr Med Chem Anticancer Agents. 2002 Jul;2(4):477-84. doi: 10.2174/1568011023353921. [Article]
- Munshi A, Kurland JF, Nishikawa T, Tanaka T, Hobbs ML, Tucker SL, Ismail S, Stevens C, Meyn RE: Histone deacetylase inhibitors radiosensitize human melanoma cells by suppressing DNA repair activity. Clin Cancer Res. 2005 Jul 1;11(13):4912-22. doi: 10.1158/1078-0432.CCR-04-2088. [Article]
- Ladiges W: The quality control theory of aging. Pathobiol Aging Age Relat Dis. 2014 May 23;4. pii: 24835. doi: 10.3402/pba.v4.24835. eCollection 2014. [Article]
- Chang MC, Chen YJ, Lian YC, Chang BE, Huang CC, Huang WL, Pan YH, Jeng JH: Butyrate Stimulates Histone H3 Acetylation, 8-Isoprostane Production, RANKL Expression, and Regulated Osteoprotegerin Expression/Secretion in MG-63 Osteoblastic Cells. Int J Mol Sci. 2018 Dec 17;19(12). pii: ijms19124071. doi: 10.3390/ijms19124071. [Article]
Drug created at September 14, 2010 16:21 / Updated at June 17, 2022 00:19