Glycerol phenylbutyrate

Identification

Name
Glycerol phenylbutyrate
Accession Number
DB08909  (DB06170)
Type
Small Molecule
Groups
Approved
Description

Glycerol phenylbutyrate is a nitrogen-binding agent. Chemically, it is a triglyceride in which three molecules of phenylbutyrate are linked to a glycerol backbone. FDA approved on February 1, 2013.

Structure
Thumb
Synonyms
  • Glyceryl Tri-4-Phenylbutyrate
  • GPB
  • GT4P
External IDs
HPN-100 / HPN100
Active Moieties
NameKindUNIICASInChI Key
Phenylacetic acidprodrugER5I1W795A103-82-2WLJVXDMOQOGPHL-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
RavictiLiquid1.1 gOralHorizon Pharma, Inc.2016-11-03Not applicableCanada
RavictiLiquid1.1 g/1mLOralHyperion Therapeutics, Inc.2013-02-282017-07-31Us
RavictiLiquid1.1 g/1mLOralHorizon Therapeutics, Llc.2013-02-28Not applicableUs
Categories
UNII
ZH6F1VCV7B
CAS number
611168-24-2
Weight
Average: 530.6512
Monoisotopic: 530.266838948
Chemical Formula
C33H38O6
InChI Key
ZSDBFLMJVAGKOU-UHFFFAOYSA-N
InChI
InChI=1S/C33H38O6/c34-31(22-10-19-27-13-4-1-5-14-27)37-25-30(39-33(36)24-12-21-29-17-8-3-9-18-29)26-38-32(35)23-11-20-28-15-6-2-7-16-28/h1-9,13-18,30H,10-12,19-26H2
IUPAC Name
1,3-bis[(4-phenylbutanoyl)oxy]propan-2-yl 4-phenylbutanoate
SMILES
O=C(CCCC1=CC=CC=C1)OCC(COC(=O)CCCC1=CC=CC=C1)OC(=O)CCCC1=CC=CC=C1

Pharmacology

Indication

Glycerol phenylbutyrate is a nitrogen-binding agent for the chronic management of adult and pediatric patients ≥2 years of age with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone.

Associated Conditions
Pharmacodynamics

Glycerol phenylbutyrate prolongs the QTc interval.

Mechanism of action

The toxic accumulation of ammonia in the blood and brain arise from urea cycle disorders in which patients are deficient in critical enzymes or transporters that are involved in the synthesis of urea from ammonia. Glycerol phenylbutyrate is a prodrug - the major metabolite, phenylacetate (PAA) is the molecule that binds to nitrogen. PAA conjugates with glutamine (which contains 2 molecules of nitrogen) via acetylation in the liver and kidneys to form phenylacetylglutamine (PAGN), which is excreted by the kidneys. PAGN, like urea, contains 2 moles of nitrogen and provides an alternate vehicle for waste nitrogen excretion.

Absorption

Glycerol phenylbutyrate is a prodrug in which phenylbutyrate (PBA) is released from the glycerol backbone by lipases in the gastrointestinal tract. PBA then undergoes beta-oxidtion to form PAA. When a single oral dose of 2.9 mL/m2 of Glycerol phenylbutyrate is given to fasting adult subjects, the pharmacokinetic parameters are as follows: Tmax: PBA = 2 hours; PAA = 4 hours; PAGN = 4 hours. Cmax: PBA = 37.0 µg/mL; PAA = 14.9 µg/mL; PAGN = 30.2 µg/mL. In healthy subjects, the hydrolysis of glycerol phenylbutyrate is incomplete, but to what extent is unknown. When glycerol phenylbutyrate is given to adult UCD patients, maximum plasma concentrations at steady state (Cmaxss) of PBA, PAA, and PAGN occurred at 8 h, 12 h, and 10 h, respectively, after the first dose in the day. Intact glycerol phenylbutyrate was not detectable in plasma in UCD patients.

Volume of distribution
Not Available
Protein binding

PBA = 80.6% to 98.0%; PAA = 37.1% to 65.6%; PAGN = 7% to 12%.

Metabolism

Pancreatic lipases hydrolyze glycerol phenylbutyrate to release PBA from the glycerol backbone. PBA undergoes β-oxidation to PAA, which is conjugated with glutamine in the liver and in the kidney through the enzyme phenylacetyl-CoA: L-glutamine-N-acetyltransferase to form PAGN.

Route of elimination

Glycerol phenylbutyrate is mainly excreted as PAGN in the urine (68.9% in adults and 66.5% in pediatric UCD patients). PAA and PBA represented minor urinary metabolites, each accounting for <1% of the administered dose of PBA.

Half life
Not Available
Clearance
Not Available
Toxicity

Most common adverse reactions in ≥10% of patients are diarrhea, flatulence, and headache.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
16-BromoepiandrosteroneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with 16-Bromoepiandrosterone.
19-norandrostenedioneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with 19-norandrostenedione.
5-androstenedioneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with 5-androstenedione.
AcebutololThe metabolism of Acebutolol can be decreased when combined with Glycerol Phenylbutyrate.
AcetaminophenAcetaminophen may decrease the excretion rate of Glycerol Phenylbutyrate which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Glycerol phenylbutyrate which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Glycerol phenylbutyrate which could result in a higher serum level.
Adefovir DipivoxilAdefovir Dipivoxil may decrease the excretion rate of Glycerol phenylbutyrate which could result in a higher serum level.
AlbendazoleThe metabolism of Albendazole can be increased when combined with Glycerol phenylbutyrate.
AlclometasoneThe therapeutic efficacy of Glycerol phenylbutyrate can be decreased when used in combination with Alclometasone.
Food Interactions
Not Available

References

General References
Not Available
External Links
KEGG Drug
D10127
PubChem Compound
10482134
PubChem Substance
175427147
ChemSpider
8657541
ChEBI
134745
ChEMBL
CHEMBL2105745
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Glycerol_phenylbutyrate
ATC Codes
A16AX09 — Glycerol phenylbutyrate
FDA label
Download (458 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentParkinson's Disease (PD)1
1CompletedDiagnosticTherapeutic Agent Toxicity1
1CompletedTreatmentHealthy Volunteers1
1CompletedTreatmentDeficiencies in enzymes of the urea cycle / Hepatic Encephalopathy1
1CompletedTreatmentMedium-chain Acyl-CoA Dehydrogenase (MCAD) Deficiency1
1, 2Not Yet RecruitingTreatmentCystic Fibrosis (CF)1
2CompletedTreatmentHepatic Encephalopathy / Liver Cirrhosis1
2CompletedTreatmentDeficiencies in enzymes of the urea cycle1
3CompletedTreatmentDeficiencies in enzymes of the urea cycle1
4CompletedTreatmentDeficiencies in enzymes of the urea cycle2
4RecruitingTreatmentDeficiencies in enzymes of the urea cycle1
Not AvailableNo Longer AvailableNot AvailableByler Disease1
Not AvailableTemporarily Not AvailableNot AvailableByler Disease1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
LiquidOral1.1 g
LiquidOral1.1 g/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8404215No2012-03-092032-03-09Us
US8642012No2010-09-222030-09-22Us
US9095559No2012-03-092032-03-09Us
US5968979No1998-07-282018-07-28Us
US9254278No2012-03-092032-03-09Us
US9561197No2010-09-222030-09-22Us
US9326966No2012-03-092032-03-09Us
US9962359No2010-09-222030-09-22Us
US9999608No2010-09-222030-09-22Us
US10045958No2010-09-222030-09-22Us
US10045959No2010-09-222030-09-22Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityInsoluble FDA label
Predicted Properties
PropertyValueSource
Water Solubility5.09e-05 mg/mLALOGPS
logP6.41ALOGPS
logP7.65ChemAxon
logS-7ALOGPS
pKa (Strongest Basic)-6.6ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area78.9 Å2ChemAxon
Rotatable Bond Count20ChemAxon
Refractivity149.74 m3·mol-1ChemAxon
Polarizability60.16 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9412
Blood Brain Barrier+0.9607
Caco-2 permeable+0.5458
P-glycoprotein substrateNon-substrate0.641
P-glycoprotein inhibitor IInhibitor0.543
P-glycoprotein inhibitor IIInhibitor0.7045
Renal organic cation transporterNon-inhibitor0.6494
CYP450 2C9 substrateNon-substrate0.8712
CYP450 2D6 substrateNon-substrate0.9079
CYP450 3A4 substrateNon-substrate0.6711
CYP450 1A2 substrateNon-inhibitor0.7516
CYP450 2C9 inhibitorInhibitor0.8526
CYP450 2D6 inhibitorNon-inhibitor0.9406
CYP450 2C19 inhibitorInhibitor0.8156
CYP450 3A4 inhibitorNon-inhibitor0.8321
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5947
Ames testNon AMES toxic0.6838
CarcinogenicityNon-carcinogens0.8278
BiodegradationReady biodegradable0.6179
Rat acute toxicity1.7748 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8718
hERG inhibition (predictor II)Non-inhibitor0.7912
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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

Taxonomy

Description
This compound belongs to the class of organic compounds known as triacylglycerols. These are glycerides consisting of three fatty acid chains covalently bonded to a glycerol molecule through ester linkages.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Glycerolipids
Sub Class
Triradylcglycerols
Direct Parent
Triacylglycerols
Alternative Parents
Tricarboxylic acids and derivatives / Fatty acid esters / Benzene and substituted derivatives / Carboxylic acid esters / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Triacyl-sn-glycerol / Tricarboxylic acid or derivatives / Fatty acid ester / Fatty acyl / Benzenoid / Monocyclic benzene moiety / Carboxylic acid ester / Carboxylic acid derivative / Organic oxygen compound / Organic oxide
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Triglyceride lipase activity
Specific Function
Not Available
Gene Name
PNLIP
Uniprot ID
P16233
Uniprot Name
Pancreatic triacylglycerol lipase
Molecular Weight
51156.48 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
General Function
Vitamin d3 25-hydroxylase activity
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 performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 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 June 19, 2013 20:19 / Updated on October 01, 2018 15:03