Identification
NameGlycerol Phenylbutyrate
Accession NumberDB08909  (DB06170)
TypeSmall Molecule
GroupsApproved
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
Product Ingredients Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
RavictiLiquid1.1 g/mLOralHyperion Therapeutics, Inc.2013-02-28Not applicableUs
RavictiLiquid1.1 g/mLOralHorizon Therapeutics, Llc.2013-02-28Not applicableUs
RavictiLiquid1.1 gOralHorizon Pharma, Inc.2016-11-03Not applicableCanada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Categories
UNIIZH6F1VCV7B
CAS number611168-24-2
WeightAverage: 530.6512
Monoisotopic: 530.266838948
Chemical FormulaC33H38O6
InChI KeyZSDBFLMJVAGKOU-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.

Structured Indications
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.

Related Articles
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 distributionNot 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 lifeNot Available
ClearanceNot Available
Toxicity

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

Affected organisms
  • Humans and other mammals
PathwaysNot Available
Pharmacogenomic Effects/ADRs Not Available
Interactions
Drug Interactions
DrugInteractionDrug group
16-BromoepiandrosteroneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with 16-Bromoepiandrosterone.Investigational
19-norandrostenedioneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with 19-norandrostenedione.Experimental, Illicit
5-androstenedioneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with 5-androstenedione.Experimental, Illicit
AlclometasoneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Alclometasone.Approved
AldosteroneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Aldosterone.Experimental
AmcinonideThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Amcinonide.Approved
AndrostenedioneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with 4-Androstenedione.Experimental, Illicit
AnecortaveThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Anecortave.Investigational
AripiprazoleThe serum concentration of Aripiprazole can be increased when it is combined with Glycerol Phenylbutyrate.Approved, Investigational
Beclomethasone dipropionateThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Beclomethasone dipropionate.Approved, Investigational
BetamethasoneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Betamethasone.Approved, Vet Approved
BudesonideThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Budesonide.Approved
CiclesonideThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Ciclesonide.Approved, Investigational
ClobetasolThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Clobetasol.Investigational
Clobetasol propionateThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Clobetasol propionate.Approved
ClocortoloneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Clocortolone.Approved
Cortisone acetateThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Cortisone acetate.Approved
DesoximetasoneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Desoximetasone.Approved
Desoxycorticosterone acetateThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Desoxycorticosterone acetate.Approved
Desoxycorticosterone PivalateThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Desoxycorticosterone Pivalate.Experimental, Vet Approved
DexamethasoneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Dexamethasone.Approved, Investigational, Vet Approved
Dexamethasone isonicotinateThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Dexamethasone isonicotinate.Vet Approved
DiflorasoneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Diflorasone.Approved
DifluocortoloneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Difluocortolone.Approved
DifluprednateThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Difluprednate.Approved
DofetilideThe serum concentration of Dofetilide can be increased when it is combined with Glycerol Phenylbutyrate.Approved
EquileninThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Equilenin.Experimental
EquilinThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Equilin.Approved
EstroneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Estrone.Approved
Estrone sulfateThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Estrone sulfate.Approved
FlibanserinThe serum concentration of Flibanserin can be increased when it is combined with Glycerol Phenylbutyrate.Approved
fluasteroneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with fluasterone.Investigational
FludrocortisoneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Fludrocortisone.Approved
FlumethasoneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Flumethasone.Approved, Vet Approved
FlunisolideThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Flunisolide.Approved, Investigational
Fluocinolone AcetonideThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Fluocinolone Acetonide.Approved, Investigational, Vet Approved
FluocinonideThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Fluocinonide.Approved, Investigational
FluocortoloneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Fluocortolone.Approved, Withdrawn
FluorometholoneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Fluorometholone.Approved
FluprednideneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Fluprednidene.Approved, Withdrawn
FluprednisoloneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Fluprednisolone.Approved
FlurandrenolideThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Flurandrenolide.Approved
Fluticasone furoateThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Fluticasone furoate.Approved
Fluticasone propionateThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Fluticasone Propionate.Approved
FormestaneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Formestane.Approved, Investigational, Withdrawn
HaloperidolThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Haloperidol.Approved
HE3286The therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with HE3286.Investigational
HydrocodoneThe serum concentration of Hydrocodone can be increased when it is combined with Glycerol Phenylbutyrate.Approved, Illicit
HydrocortisoneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Hydrocortisone.Approved, Vet Approved
IstaroximeThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Istaroxime.Investigational
LomitapideThe serum concentration of Lomitapide can be increased when it is combined with Glycerol Phenylbutyrate.Approved
ME-609The therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with ME-609.Investigational
MedrysoneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Medrysone.Approved
MelengestrolThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Melengestrol.Vet Approved
MethylprednisoloneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Methylprednisolone.Approved, Vet Approved
MometasoneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Mometasone.Approved, Vet Approved
NCX 1022The therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with NCX 1022.Investigational
NimodipineThe serum concentration of Nimodipine can be increased when it is combined with Glycerol Phenylbutyrate.Approved
Oleoyl-estroneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Oleoyl estrone.Investigational
ParamethasoneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Paramethasone.Approved
PimozideThe serum concentration of Pimozide can be increased when it is combined with Glycerol Phenylbutyrate.Approved
PrasteroneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Prasterone.Approved, Nutraceutical
Prasterone sulfateThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with dehydroepiandrosterone sulfate.Investigational
PrednicarbateThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Prednicarbate.Approved
PrednisoloneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Prednisolone.Approved, Vet Approved
PrednisoneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Prednisone.Approved, Vet Approved
PregnenoloneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Pregnenolone.Experimental
ProbenecidThe serum concentration of the active metabolites of Glycerol Phenylbutyrate can be increased when Glycerol Phenylbutyrate is used in combination with Probenecid.Approved
RimexoloneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Rimexolone.Approved
TixocortolThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Tixocortol.Approved
TizanidineThe serum concentration of Tizanidine can be increased when it is combined with Glycerol Phenylbutyrate.Approved
TriamcinoloneThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Triamcinolone.Approved, Vet Approved
Valproic AcidThe therapeutic efficacy of Glycerol Phenylbutyrate can be decreased when used in combination with Valproic Acid.Approved, Investigational
Food InteractionsNot Available
References
Synthesis ReferenceNot Available
General ReferencesNot Available
External Links
ATC CodesA16AX09 — Glycerol phenylbutyrate
AHFS Codes
  • 40:10
PDB EntriesNot Available
FDA labelDownload (458 KB)
MSDSNot Available
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 cycle1
Not AvailableNo Longer AvailableNot AvailableByler Disease1
Not AvailableTemporarily Not AvailableNot AvailableByler Disease1
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
LiquidOral1.1 g/mL
LiquidOral1.1 g
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8404215 No2012-03-092032-03-09Us
US8642012 No2010-09-222030-09-22Us
US9095559 No2012-03-092032-03-09Us
US5968979 No1998-07-282018-07-28Us
US9254278 No2012-03-092032-03-09Us
US9561197 No2010-09-222030-09-22Us
US9326966 No2012-03-092032-03-09Us
Properties
StateSolid
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
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
Taxonomy
DescriptionThis compound belongs to the class of chemical entities known as triacylglycerols. These are glycerides consisting of three fatty acid chains covalently bonded to a glycerol molecule through ester linkages.
KingdomChemical entities
Super ClassOrganic compounds
ClassLipids and lipid-like molecules
Sub ClassGlycerolipids
Direct ParentTriacylglycerols
Alternative ParentsTricarboxylic acids and derivatives / Fatty acid esters / Benzene and substituted derivatives / Carboxylic acid esters / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
SubstituentsTriacyl-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 FrameworkAromatic homomonocyclic compounds
External DescriptorsNot 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
inhibitor
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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
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:
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 unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N...
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 antidepressants.
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 September 01, 2017 12:00