Uridine triacetate

Identification

Name
Uridine triacetate
Accession Number
DB09144  (DB05425)
Type
Small Molecule
Groups
Approved, Investigational
Description

Uridine triacetate, formerly known as vistonuridine, is an orally active prodrug of the naturally occurring nucleoside uridine. It is used for the treatment of hereditary orotic aciduria (Xuriden), or for the emergency treatment of fluorouracil or capecitabine overdose or toxicity (Vistogard). It is provided in the prodrug form as uridine triacetate as this form delivers 4- to 6-fold more uridine into the systemic circulation compared to equimolar doses of uridine itself.

When used for the treatment or prevention of toxicity associated with fluorouracil and other antimetabolites, uridine triacetate is utilized for its ability to compete with 5-fluorouracil (5-FU) metabolites for incorporation into the genetic material of non-cancerous cells. It reduces toxicity and cell-death associated with two cytotoxic intermediates: 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). Normally, FdUMP inhibits thymidylate synthase required for thymidine synthesis and DNA replication and repair while FUTP incorporates into RNA resulting in defective strands. As a result, these metabolites are associated with various unpleasant side effects such as neutropenia, mucositis, diarrhea, and hand–foot syndrome. Like many other neoplastic agents, these side effects limit the doses of 5-FU that can be administered, which also affects the efficacy for treatment. By pre-administering with uridine (as the prodrug uridine triacetate), higher doses of 5-FU can be given allowing for improved efficacy and a reduction in toxic side effects [3]. It can also be used as a rescue therapy if severe side effects present within 96 hours after initiation of therapy.

Uridine triacetate is also used for the treatment of hereditary orotic aciduria, also known as uridine monophosphate synthase deficiency. This rare congenital autosomal recessive disorder of pyrimidine metabolism is caused by a defect in uridine monophosphate synthase (UMPS), a bifunctional enzyme that catalyzes the final two steps of the de novo pyrimidine biosynthetic pathway. As a result of UMPS deficiency, patients experience a systemic deficiency of pyrimidine nucleotides, accounting for most symptoms of the disease. Additionally, orotic acid from the de novo pyrimidine pathway that cannot be converted to UMP is excreted in the urine, accounting for the common name of the disorder, orotic aciduria. Furthermore, orotic acid crystals in the urine can cause episodes of obstructive uropathy. When administered as the prodrug uridine triacetate, uridine can be used by essentially all cells to make uridine nucleotides, which compensates for the genetic deficiency in synthesis in patients with hereditary orotic aciduria. When intracellular uridine nucleotides are restored into the normal range, overproduction of orotic acid is reduced by feedback inhibition, so that urinary excretion of orotic acid is also reduced.

Structure
Thumb
Synonyms
  • 2',3',5'-tri-O-acetyluridine
  • 2',3',5'-Triacetyluridine
  • Tri-O-acetyluridine
  • Triacetyl uridine
  • Triacetyluridine
  • Uridine 2',3',5'-triacetate
  • Vistonuridine
External IDs
PN 401 / PN-401 / PN401 / RG 2133 / RG-2133 / RG2133
Active Moieties
NameKindUNIICASInChI Key
UridineprodrugWHI7HQ7H8558-96-8DRTQHJPVMGBUCF-XVFCMESISA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
VistogardGranule951 mg/1gOralWellstat Therapeutics2016-03-01Not applicableUs
XuridenGranule951 mg/1gOralWellstat Therapeutics2015-09-08Not applicableUs
Categories
UNII
2WP61F175M
CAS number
4105-38-8
Weight
Average: 370.314
Monoisotopic: 370.101230168
Chemical Formula
C15H18N2O9
InChI Key
AUFUWRKPQLGTGF-FMKGYKFTSA-N
InChI
InChI=1S/C15H18N2O9/c1-7(18)23-6-10-12(24-8(2)19)13(25-9(3)20)14(26-10)17-5-4-11(21)16-15(17)22/h4-5,10,12-14H,6H2,1-3H3,(H,16,21,22)/t10-,12-,13-,14-/m1/s1
IUPAC Name
[(2R,3R,4R,5R)-3,4-bis(acetyloxy)-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)oxolan-2-yl]methyl acetate
SMILES
CC(=O)OC[C@H]1O[C@H]([C@H](OC(C)=O)[C@@H]1OC(C)=O)N1C=CC(=O)NC1=O

Pharmacology

Indication

Marketed as the product Xuriden (FDA), uridine triacetate is indicated for the treatment of hereditary orotic aciduria.

Marketed as the product Vistogard (FDA), uridine triacetate is indicated for the emergency treatment of adult and pediatric patients in the following situations: following a fluorouracil or capecitabine overdose regardless of the presence of symptoms; or who exhibit early-onset, severe or life-threatening toxicity affecting the cardiac or central nervous system, and/or early-onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of fluorouracil or capecitabine administration.

Associated Conditions
Pharmacodynamics
Not Available
Mechanism of action

Uridine triacetate is a synthetic uridine pro-drug that is converted to uridine in vivo. When used for the treatment or prevention of toxicity associated with fluorouracil and other antimetabolites, uridine triacetate is utilized for its ability to compete with 5-fluorouracil (5-FU) metabolites for incorporation into the genetic material of non-cancerous cells. It reduces toxicity and cell-death associated with two cytotoxic intermediates: 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). By pre-administering with uridine (as the prodrug uridine triacetate), higher doses of 5-FU can be given allowing for improved efficacy and a reduction in toxic side effects [3] such as neutropenia, mucositis, diarrhea, and hand–foot syndrome.

Uridine triacetate is also used for replacement therapy in the treatment of hereditary orotic aciduria, also known as uridine monophosphate synthase (UMPS) deficiency. As a result of UMPS deficiency, patients experience a systemic deficiency of pyrimidine nucleotides, accounting for most symptoms of the disease. Additionally, orotic acid from the de novo pyrimidine pathway that cannot be converted to UMP is excreted in the urine, accounting for the common name of the disorder, orotic aciduria. Furthermore, orotic acid crystals in the urine can cause episodes of obstructive uropathy. When administered as the prodrug uridine triacetate, uridine can be used by essentially all cells to make uridine nucleotides, which compensates for the genetic deficiency in synthesis in patients with hereditary orotic aciduria.

Absorption

Maximum concentrations of uridine in plasma following oral administration are generally achieved within 2 to 3 hours.

Volume of distribution

Circulating uridine is taken up into mammalian cells via specific nucleoside transporters, and also crosses the blood brain barrier.

Protein binding
Not Available
Metabolism

Following oral administration, uridine triacetate is deacetylated by nonspecific esterases present throughout the body, yielding uridine in the circulation.

Route of elimination

Uridine can be excreted via the kidneys, but is also metabolized by normal pyrimidine catabolic pathways present in most tissues.

Half life

2 to 2.5 hours

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

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Klivenyi P, Gardian G, Calingasan NY, Yang L, von Borstel R, Saydoff J, Browne SE, Beal MF: Neuroprotective effects of oral administration of triacetyluridine against MPTP neurotoxicity. Neuromolecular Med. 2004;6(2-3):87-92. [PubMed:15970626]
  2. McEvilly M, Popelas C, Tremmel B: Use of uridine triacetate for the management of fluorouracil overdose. Am J Health Syst Pharm. 2011 Oct 1;68(19):1806-9. doi: 10.2146/ajhp100434. [PubMed:21930638]
  3. Saif MW, von Borstel R: 5-Fluorouracil dose escalation enabled with PN401 (triacetyluridine): toxicity reduction and increased antitumor activity in mice. Cancer Chemother Pharmacol. 2006 Jul;58(1):136-42. Epub 2005 Sep 27. [PubMed:16187114]
  4. Saydoff JA, Liu LS, Garcia RA, Hu Z, Li D, von Borstel RW: Oral uridine pro-drug PN401 decreases neurodegeneration, behavioral impairment, weight loss and mortality in the 3-nitropropionic acid mitochondrial toxin model of Huntington's disease. Brain Res. 2003 Dec 19;994(1):44-54. [PubMed:14642447]
External Links
KEGG Drug
D09985
PubChem Compound
20058
PubChem Substance
310265057
ChemSpider
18897
ChEBI
90914
ChEMBL
CHEMBL2107381
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Uridine_triacetate
FDA label
Download (919 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1TerminatedTreatmentMitochondrial Diseases1
1TerminatedTreatmentTumors, Solid1
2Active Not RecruitingTreatmentHereditary Orotic Aciduria1
2CompletedTreatmentEsophageal Cancers / Malignant Neoplasm of Stomach1
3CompletedTreatmentDrug/Agent Toxicity by Tissue/Organ / Malignant Neoplasm of Pancreas1
Not AvailableApproved for MarketingNot AvailableToxicity Due to Chemotherapy1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
GranuleOral951 mg/1g
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7776838No2007-08-172027-08-17Us
US5968914No1996-10-192016-10-19Us
US6258795No1998-07-102018-07-10Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility14.6 mg/mLALOGPS
logP0.01ALOGPS
logP-1.1ChemAxon
logS-1.4ALOGPS
pKa (Strongest Acidic)9.7ChemAxon
pKa (Strongest Basic)-4.3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area137.54 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity80.02 m3·mol-1ChemAxon
Polarizability34.34 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

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 pyrimidine nucleosides. These are compounds comprising a pyrimidine base attached to a ribosyl or deoxyribosyl moiety.
Kingdom
Organic compounds
Super Class
Nucleosides, nucleotides, and analogues
Class
Pyrimidine nucleosides
Sub Class
Not Available
Direct Parent
Pyrimidine nucleosides
Alternative Parents
Glycosylamines / Tricarboxylic acids and derivatives / Pyrimidones / Hydropyrimidines / Monosaccharides / Vinylogous amides / Heteroaromatic compounds / Tetrahydrofurans / Carboxylic acid esters / Lactams
show 8 more
Substituents
Pyrimidine nucleoside / Glycosyl compound / N-glycosyl compound / Tricarboxylic acid or derivatives / Pyrimidone / Hydropyrimidine / Monosaccharide / Pyrimidine / Vinylogous amide / Heteroaromatic compound
show 17 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Drug created on October 01, 2015 09:39 / Updated on November 02, 2018 06:59