Phenylbutyric acid
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
A monocarboxylic acid the structure of which is that of butyric acid substituted with a phenyl group at C-4. It is a histone deacetylase inhibitor that displays anticancer activity. It inhibits cell proliferation, invasion and migration and induces apoptosis in glioma cells. It also inhibits protein isoprenylation, depletes plasma glutamine, increases production of foetal haemoglobin through transcriptional activation of the γ-globin gene and affects hPPARγ activation.
- 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
Adjunctive therapy for the management of chronic urea cycle disorders due to deficiencies in carbamylphosphate (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase. it is indicated in all neonatal- onset efficiency presenting within the first 28 days of life. Also indicated in patients with late-onset, presenting after the first month of life with a history of hyperammonemic encephalopathy.
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- Contraindications & Blackbox Warnings
Contraindications & Blackbox WarningsWith our commercial data, access important information on dangerous risks, contraindications, and adverse effects.Our Blackbox Warnings cover Risks, Contraindications, and Adverse Effects- Pharmacodynamics
Decreases elevated plasma ammonia glutamine levels
- Mechanism of action
Sodium phenylbutyrate is a pro-drug that is metabolized to the active compound phenylacetate. Phenylacetate conjuages with glutamine via acetylation reaction to form the product phenylacetylglutamine, which is excreted by the kidneys. This provides an alternative mechanism for waste nitrogen excretion.
Target Actions Organism UAromatic-amino-acid aminotransferase Not Available Paracoccus denitrificans UThermolysin Not Available Bacillus thermoproteolyticus - Absorption
Under fasting condition the Cmax of a single orally ingested 5g tablet and 5g powder after 1 hour are respectively 218mcg/ml and 195mcg/ml. The effect of food on phenylbutyrate absorption is still unknown.
- Volume of distribution
The volume of distribution of phenylbutyrate is 0.2 l/kg.
- Protein binding
phenylbutyrate and Phenylacetate concentrations in the plasma were determined by high-performance liquid chromatography. Both drugs exhibited concentration-dependent binding. Results showed sodium phenylacetate to have a higher free fraction than sodium phenylbutyrate at corresponding concentrations (> 0.442 +/- 0.008 and > 0.188 +/- 0.001, respectively). Both have high free fractions in plasma.
- Metabolism
The overall disposition of sodium phenylbutyrate and its metabolites has not been characterized fully. However, the drug is known to be metabolized to phenylacetate and subsequently to phenylacetylglutamine. Metabolism of phenylbutyrate occurs mainly in liver and kidney.
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- Route of elimination
The major route of elimination is the kidneys as phenylacetylglutamine.
- Half-life
For sodium phenylbutyrate the half life is 0.77 hours. For phenylacetate the half life is 1.15 hours.
- Clearance
Within 24 hours 80-100% of the administered dose in eliminated in the urine as pheylacetylglutamine.
- Adverse Effects
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Clinical adverse reaction: In females who were menstruating, 23% reported amenorrhea or menstrual dysfunction. In all patients, 4% reported a decreased appetite, and body odor issues, and 3% of patients report a taste aversion. Other adverse events that occurred in less than 2% of patients were abdominal pain, gastritis, nausea and vomiting, constipation, rectal bleeding, peptic ulcer disease, pancreatitis, aplastic anemia, ecchymosis, arrhythmia, edema, renal tubular acidosis, depressions, skin rash, headache, syncope, and weight gain occurring in at least one patient. Laboratory adverse events: Changes to baseline laboratory values were also observed. The events include: acidosis (14%), alkalosis and hyperchloremia (7%), hypophosphatemia (6%), hyperuricemia and hyperphosphatemia (2%), hypernatremia and hypokalemia (1%), hypoalbuminemia (11%), decreased total protein (3%), increase alkaline phosphate (6%), increased liver transaminases (4%), hyperbilirubinemia (1%), anemia (9%), leukopenia and leukocytosis (4%), thrombocytopenia (3%) and thrombocytosis (1%).
- 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.
Products
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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 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 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 - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Sodium Phenylbutyrate Powder 0.94 g/1g Oral Sigma Pharm Laboratories, Llc 2011-11-30 Not applicable US Sodium Phenylbutyrate Tablet 500 mg/1 Oral Mikart, LLC 2011-11-18 2011-11-19 US 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
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
- External Links
- Human Metabolome Database
- HMDB0000543
- KEGG Drug
- D05868
- PubChem Compound
- 4775
- PubChem Substance
- 310264895
- ChemSpider
- 4611
- 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
- FDA label
- Download (91.6 KB)
- MSDS
- Download (220 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Completed Health Services Research Diabetes / Insulin Resistance 1 4 Recruiting Treatment Deficiencies in enzymes of the urea cycle 1 3 Completed Treatment Deficiencies in enzymes of the urea cycle 1 2 Active Not Recruiting 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 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 2 Completed Treatment Leukemias 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Granule Oral 940 mg/g Tablet Oral Tablet Oral 500 mg Powder Oral 0.94 g/1g Tablet Oral 500 mg/1 Granule Oral Granule Oral 483 mg / g Granule Oral 483 mg/g - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) >150 MSDS water solubility 100mM MSDS - 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
- Organism
- Bacillus thermoproteolyticus
- Pharmacological action
- Unknown
- General Function
- Metalloendopeptidase activity
- Specific Function
- Extracellular zinc metalloprotease.
- Gene Name
- npr
- Uniprot ID
- P00800
- Uniprot Name
- Thermolysin
- Molecular Weight
- 60103.515 Da
References
- 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]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
- Gene Name
- CYP2D6
- Uniprot ID
- P10635
- Uniprot Name
- Cytochrome P450 2D6
- Molecular Weight
- 55768.94 Da
Drug created on September 14, 2010 16:21 / Updated on June 12, 2020 16:52