Identification

Name
Phenylbutyric acid
Accession Number
DB06819  (EXPT00947, DB02000, DB12600)
Type
Small Molecule
Groups
Approved, Investigational
Description

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.

Structure
Thumb
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
Product Ingredients
IngredientUNIICASInChI Key
Sodium phenylbutyrateNT6K61736T1716-12-7VPZRWNZGLKXFOE-UHFFFAOYSA-M
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AmmonapsGranule940 mg/gOralSwedish Orphan Biovitrum Ab1999-12-08Not applicableEu
AmmonapsTablet500 mgOralSwedish Orphan Biovitrum Ab1999-12-08Not applicableEu
AmmonapsGranule940 mg/gOralSwedish Orphan Biovitrum Ab1999-12-08Not applicableEu
AmmonapsTablet500 mgOralSwedish Orphan Biovitrum Ab1999-12-08Not applicableEu
BuphenylPowder0.94 g/1gOralHyperion Therapeutics, Inc.1996-04-302016-11-29Us
BuphenylTablet500 mg/1OralUcyclyd Pharma Inc.1996-05-132015-02-28Us
BuphenylPowder0.94 g/1gOralHorizon Pharma, Inc.1996-04-30Not applicableUs
BuphenylTablet500 mg/1OralHyperion Therapeutics, Inc.1996-05-132016-11-29Us
BuphenylTablet500 mg/1OralHorizon Pharma, Inc.1996-05-13Not applicableUs
BuphenylPowder0.94 g/1gOralUcyclyd Pharma Inc.1996-04-302015-02-28Us
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Sodium PhenylbutyratePowder0.94 g/1gOralSigma Pharm Laboratories, Llc2011-11-30Not applicableUs
Sodium PhenylbutyrateTablet500 mg/1OralMikart, Inc.2011-11-18Not applicableUs
Sodium PhenylbutyratePowder0.94 g/1gOralPar Pharmaceutical2016-08-31Not applicableUs49884 00620180907 15195 1sffcv4
Sodium PhenylbutyrateTablet500 mg/1OralPar Pharmaceutical2016-04-29Not applicableUs
International/Other Brands
Ammonaps (Swedish Swedish Orphan International) / triButyrate (Fyrlklövern Scandinavia)
Categories
UNII
7WY7YBI87E
CAS number
1821-12-1
Weight
Average: 164.2011
Monoisotopic: 164.083729628
Chemical Formula
C10H12O2
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

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.

Associated Conditions
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.

TargetActionsOrganism
UAromatic-amino-acid aminotransferaseNot AvailableParacoccus denitrificans
UThermolysinNot AvailableBacillus 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.

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.

Toxicity

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%).

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
16-BromoepiandrosteroneThe therapeutic efficacy of Phenylbutyric acid can be decreased when used in combination with 16-Bromoepiandrosterone.
19-norandrostenedioneThe therapeutic efficacy of Phenylbutyric acid can be decreased when used in combination with 19-norandrostenedione.
5-androstenedioneThe therapeutic efficacy of Phenylbutyric acid can be decreased when used in combination with 5-androstenedione.
AcebutololThe metabolism of Acebutolol can be decreased when combined with Phenylbutyric acid.
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Phenylbutyric acid.
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Phenylbutyric acid.
AlclometasoneThe therapeutic efficacy of Phenylbutyric acid can be decreased when used in combination with Alclometasone.
AldosteroneThe therapeutic efficacy of Phenylbutyric acid can be decreased when used in combination with Aldosterone.
AmcinonideThe therapeutic efficacy of Phenylbutyric acid can be decreased when used in combination with Amcinonide.
AmitriptylineThe metabolism of Amitriptyline can be decreased when combined with Phenylbutyric acid.
Food Interactions
Not Available

References

General References
  1. product info [Link]
  2. FDA label [Link]
External Links
Human Metabolome Database
HMDB0000543
KEGG Drug
D05868
PubChem Compound
4775
PubChem Substance
310264895
ChemSpider
4611
ChEBI
41500
ChEMBL
CHEMBL1469
HET
CLT
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Sodium_phenylbutyrate
ATC Codes
A16AX03 — 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
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHealthy Volunteers1
1CompletedTreatmentLeukemias / Myelodysplastic Syndromes / Myelodysplastic/Myeloproliferative Diseases2
1CompletedTreatmentMalignant Lymphomas / Small Intestine Cancer / Unspecified Adult Solid Tumor, Protocol Specific1
1CompletedTreatmentMalignant Lymphomas / Unspecified Adult Solid Tumor, Protocol Specific1
1CompletedTreatmentNeoplasms, Brain / Neuroblastomas1
1, 2CompletedBasic ScienceCystic Fibrosis (CF)1
1, 2CompletedTreatmentAmyotrophic Lateral Sclerosis (ALS)1
1, 2CompletedTreatmentSpinal Muscular Atrophy (SMA)1
1, 2TerminatedBasic ScienceCystic Fibrosis (CF)1
1, 2TerminatedTreatmentMucinous Adenocarcinoma of the Colon / Mucinous Adenocarcinoma of the Rectum / Recurrent Colon Cancer / Recurrent Rectal Cancer / Signet Ring Adenocarcinoma of the Colon / Signet Ring Adenocarcinoma of the Rectum / Stage IVA Colon Cancer / Stage IVA Rectal Cancer / Stage IVB Colon Cancer / Stage IVB Rectal Cancer1
1, 2TerminatedTreatmentSpinal Muscular Atrophy Type I1
1, 2TerminatedTreatmentSpinal Muscular Atrophy Type II / Spinal Muscular Atrophy Type III1
2CompletedTreatmentAmino Acid Metabolism, Inborn Errors1
2CompletedTreatmentAmino Acid Metabolism, Inborn Errors / Argininosuccinic Aciduria / Deficiencies in enzymes of the urea cycle1
2CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
2CompletedTreatmentHuntington's Disease (HD)1
2CompletedTreatmentLeukemias1
2CompletedTreatmentLeukemias / Lung Cancers / Malignant Lymphomas / Multiple Myeloma and Plasma Cell Neoplasm / Myelodysplastic Syndromes / Prostate Cancer1
2CompletedTreatmentNeoplasms, Brain1
2CompletedTreatmentPulmonary Tuberculosis (TB)1
2CompletedTreatmentTuberculosis, Pulmonary1
2CompletedTreatmentDeficiencies in enzymes of the urea cycle2
2RecruitingTreatmentAlzheimer's Disease (AD)1
2RecruitingTreatmentAmyotrophic Lateral Sclerosis (ALS) / Central Nervous System Diseases / Motor Neurone Disease / Nervous System Diseases / Neurodegenerative Disorders / Neuromuscular Diseases / Spinal Cord Diseases / TDP-43 Proteinopathies1
2TerminatedTreatmentThalassemia Major (TM)1
2Unknown StatusTreatmentHead and Neck Carcinoma / Lymphoproliferative Disorders / Malignant Lymphomas / Malignant Neoplasm of Stomach1
2WithdrawnTreatmentSpinocerebellar Ataxia Type 31
2, 3Active Not RecruitingTreatmentMaple Syrup Urine Disease1
3CompletedTreatmentDeficiencies in enzymes of the urea cycle2
4CompletedHealth Services ResearchDiabetes Mellitus (DM) / Insulin Resistance1
4RecruitingTreatmentDeficiencies in enzymes of the urea cycle1
Not AvailableCompletedBasic ScienceBMI >30 kg/m2 / Diabetes Mellitus (DM) / Insulin Resistance1
Not AvailableCompletedOtherUCDs (The Data May be Helpful in the Treatment of UCDs.) / Urea Cycle Disorders, Inborn1
Not AvailableNo Longer AvailableNot AvailableByler Disease1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
GranuleOral940 mg/g
TabletOral500 mg
PowderOral0.94 g/1g
TabletOral500 mg/1
GranuleOral483 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)>150MSDS
water solubility100mMMSDS
Predicted Properties
PropertyValueSource
Water Solubility0.513 mg/mLALOGPS
logP2.29ALOGPS
logP2.5ChemAxon
logS-2.5ALOGPS
pKa (Strongest Acidic)4.81ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area37.3 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity46.57 m3·mol-1ChemAxon
Polarizability17.99 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - EI-BGC-MSsplash10-0udl-7900000000-3308656352d708576a12
MS/MS Spectrum - Quattro_QQQ 10V, NegativeLC-MS/MSsplash10-03di-4900000000-2b18919d21183949b0f0
MS/MS Spectrum - Quattro_QQQ 25V, NegativeLC-MS/MSsplash10-0006-9000000000-6e1432dc108281f8c5fb
MS/MS Spectrum - Quattro_QQQ 40V, NegativeLC-MS/MSsplash10-0006-9100000000-9477dfafb0c27b1670ab
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
1H NMR Spectrum1D NMRNot Applicable
[1H,13C] 2D NMR Spectrum2D NMRNot Applicable

Taxonomy

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
Monocyclic benzene moiety / Monocarboxylic acid or derivatives / Carboxylic acid / Carboxylic acid derivative / Organic oxygen compound / Organic oxide / Hydrocarbon derivative / Organooxygen compound / Carbonyl group / Aromatic homomonocyclic compound
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
monocarboxylic acid (CHEBI:41500)

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
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. 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. [PubMed:17016423]
  3. 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. [PubMed:10592235]
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
  1. 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. [PubMed:10592235]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
Kind
Protein
Organism
Human
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 10:21 / Updated on August 02, 2018 05:40