Glycerol phenylbutyrate

Identification

Summary

Glycerol phenylbutyrate is a nitrogen-binding agent used to manage patients with urea cycle disorders who cannot be sufficiently managed amino acid supplementation and/or dietary restrictions.

Brand Names

Ravicti

Generic Name

Glycerol phenylbutyrate

DrugBank Accession Number

DB08909

Background

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.

Type

Small Molecule

Groups

Approved

Structure

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Glycerol phenylbutyrate (DB08909)

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Weight

Average: 530.6512
Monoisotopic: 530.266838948

Chemical Formula

C₃₃H₃₈O₆

Synonyms

• Glycerol phenylbutyrate
• Glyceryl Tri-4-Phenylbutyrate
• GPB
• GT4P

External IDs

• HPN-100
• HPN100

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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.

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Management of	Urea cycle disorders		••••••••••••		•••••••••• •••••••• •• ••••

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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

Adverse Effects

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Toxicity

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

Pathways

Not Available

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Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
Integrate drug-drug interactions in your software
Abacavir	Abacavir may decrease the excretion rate of Glycerol phenylbutyrate which could result in a higher serum level.
Abemaciclib	The metabolism of Abemaciclib can be increased when combined with Glycerol phenylbutyrate.
Acalabrutinib	The metabolism of Acalabrutinib can be increased when combined with Glycerol phenylbutyrate.
Acebutolol	The metabolism of Acebutolol can be decreased when combined with Glycerol phenylbutyrate.
Aceclofenac	Aceclofenac may decrease the excretion rate of Glycerol phenylbutyrate which could result in a higher serum level.

Food Interactions

• Take with food.

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Active Moieties

Name	Kind	UNII	CAS	InChI Key
Phenylacetic acid	prodrug	ER5I1W795A	103-82-2	WLJVXDMOQOGPHL-UHFFFAOYSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Ravicti	Liquid	1.1 g / mL	Oral	Horizon Pharma, Inc.	2016-11-03	Not applicable
Ravicti	Liquid	1.1 g/1mL	Oral	Horizon Therapeutics USA, Inc.	2013-02-28	Not applicable
Ravicti		1.1 g/ml		Immedica Pharma Ab	2020-12-21	Not applicable
Ravicti	Liquid	1.1 g/1mL	Oral	Hyperion Therapeutics, Inc.	2013-02-28	2017-07-31

Categories

ATC Codes

A16AX09 — Glycerol phenylbutyrate

• A16AX — Various alimentary tract and metabolism products
• A16A — OTHER ALIMENTARY TRACT AND METABOLISM PRODUCTS
• A16 — OTHER ALIMENTARY TRACT AND METABOLISM PRODUCTS
• A — ALIMENTARY TRACT AND METABOLISM

Drug Categories

• Acids, Carbocyclic
• Alcohols
• Alimentary Tract and Metabolism
• Carbohydrates
• Cytochrome P-450 CYP2D6 Inhibitors
• Cytochrome P-450 CYP2D6 Inhibitors (strong)
• Cytochrome P-450 CYP3A Inducers
• Cytochrome P-450 CYP3A4 Inducers
• Cytochrome P-450 CYP3A4 Inducers (weak)
• Cytochrome P-450 Enzyme Inducers
• Cytochrome P-450 Enzyme Inhibitors
• Drugs that are Mainly Renally Excreted
• Nitrogen Binding Agent
• Sugar Alcohols
• Triose Sugar Alcohols
• 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 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

Aromatic homomonocyclic compound / Benzenoid / Carbonyl group / Carboxylic acid derivative / Carboxylic acid ester / Fatty acid ester / Fatty acyl / Hydrocarbon derivative / Monocyclic benzene moiety / Organic oxide

Molecular Framework

Aromatic homomonocyclic compounds

External Descriptors

Not Available

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

ZH6F1VCV7B

CAS number

611168-24-2

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

References

General References

1. FDA Approved Drug Products: RAVICTI (glycerol phenylbutyrate) oral liquid [Link]

External Links

KEGG Drug

D10127

PubChem Compound

10482134

PubChem Substance

175427147

ChemSpider

8657541

RxNav

1368451

ChEBI

134745

ChEMBL

CHEMBL2105745

RxList

RxList Drug Page

Drugs.com

Drugs.com Drug Page

Wikipedia

Glycerol_phenylbutyrate

FDA label

Download (458 KB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	Disorders of urea cycle metabolism	3
3	Completed	Treatment	Disorders of urea cycle metabolism	3
2	Completed	Treatment	Cirrhosis of the Liver / Hepatic Encephalopathy (HE)	1
2	Completed	Treatment	Disorders of urea cycle metabolism	2
2	Recruiting	Treatment	Cortical Basal Syndrome (CBS)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Liquid	Oral	1.1 G/ML
Liquid	Oral	1.1 g / mL
Liquid	Oral	1.1 g/1mL

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US8404215	No	2013-03-26	2032-03-09
US8642012	No	2014-02-04	2030-09-22
US9095559	No	2015-08-04	2032-03-09
US5968979	No	1999-10-19	2018-07-28
US9254278	No	2016-02-09	2032-03-09
US9561197	No	2017-02-07	2030-09-22
US9326966	No	2016-05-03	2032-03-09
US9962359	No	2018-05-08	2030-09-22
US9999608	No	2018-06-19	2030-09-22
US10045958	No	2018-08-14	2030-09-22
US10045959	No	2018-08-14	2030-09-22
US10183003	No	2019-01-22	2030-09-22
US10183002	No	2019-01-22	2030-09-22
US10183004	No	2019-01-22	2030-09-22
US10183006	No	2019-01-22	2030-09-22
US10183005	No	2019-01-22	2030-09-22
US10668040	No	2020-06-02	2030-09-22

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	Insoluble	FDA label

Predicted Properties

Property	Value	Source
Water Solubility	5.09e-05 mg/mL	ALOGPS
logP	6.41	ALOGPS
logP	7.65	Chemaxon
logS	-7	ALOGPS
pKa (Strongest Basic)	-6.6	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	3	Chemaxon
Hydrogen Donor Count	0	Chemaxon
Polar Surface Area	78.9 Å2	Chemaxon
Rotatable Bond Count	20	Chemaxon
Refractivity	149.74 m3·mol-1	Chemaxon
Polarizability	60.16 Å3	Chemaxon
Number of Rings	3	Chemaxon
Bioavailability	0	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	0.9412
Blood Brain Barrier	+	0.9607
Caco-2 permeable	+	0.5458
P-glycoprotein substrate	Non-substrate	0.641
P-glycoprotein inhibitor I	Inhibitor	0.543
P-glycoprotein inhibitor II	Inhibitor	0.7045
Renal organic cation transporter	Non-inhibitor	0.6494
CYP450 2C9 substrate	Non-substrate	0.8712
CYP450 2D6 substrate	Non-substrate	0.9079
CYP450 3A4 substrate	Non-substrate	0.6711
CYP450 1A2 substrate	Non-inhibitor	0.7516
CYP450 2C9 inhibitor	Inhibitor	0.8526
CYP450 2D6 inhibitor	Non-inhibitor	0.9406
CYP450 2C19 inhibitor	Inhibitor	0.8156
CYP450 3A4 inhibitor	Non-inhibitor	0.8321
CYP450 inhibitory promiscuity	High CYP Inhibitory Promiscuity	0.5947
Ames test	Non AMES toxic	0.6838
Carcinogenicity	Non-carcinogens	0.8278
Biodegradation	Ready biodegradable	0.6179
Rat acute toxicity	1.7748 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.8718
hERG inhibition (predictor II)	Non-inhibitor	0.7912

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0159-0509260000-e79103265ff8c23c0adb
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0n4i-3529060000-994f2f377370221b9f71
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-014i-0914100000-ba82a6d00ce319045900
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0pb9-4393000000-9d2c2f22ef1afa2cd528
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-1000-4893000000-5ecd7bef76011e784fc3
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0le9-0901000000-a1c2a6696ee53089d7f5

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	252.9118537	predicted	DarkChem Lite v0.1.0
[M-H]-	219.36687	predicted	DeepCCS 1.0 (2019)
[M+H]+	254.6247537	predicted	DarkChem Lite v0.1.0
[M+H]+	221.72487	predicted	DeepCCS 1.0 (2019)
[M+Na]+	254.8997537	predicted	DarkChem Lite v0.1.0
[M+Na]+	228.92174	predicted	DeepCCS 1.0 (2019)

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Drug created at June 20, 2013 02:19 / Updated at March 24, 2022 01:23