In HeLa cells overexpressing ENT1 and ENT2, uridine triacetate inhibits [3H]uridine absorption with IC50 values of 228.4 μM and 28.4 μM, respectively [4].

The oral administration of uridine triacetate (2 g/kg) once every 8 hours for a total of 15 doses has been shown to enhance survival and decrease toxicity in 5-FU overdose mice [3]. Oral administration of uridine triacetate (2 g/kg) once every 8 hours for a total of 15 doses has been shown to decrease 5-FU toxicity and increase the survival rate of DPD-deficient mice [3].

Animal/Disease Models: 5-FU overdose (intraperitoneal, 300 mg/kg) BALB/c mouse model [3]
Doses: 2 g/kg
Route of Administration: po (oral gavage), once every 8 hrs (hrs (hours)), a total of 15 total doses.
Experimental Results: The survival rates of the groups initiated within 24, 48, 72, 96, 120 and 144 hrs (hrs (hours)) increased to 90%, 60%, 30%, 20%, 0% and 0% respectively.

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Animal/Disease Models: 5-ethynyluracil-induced (intraperitoneal (ip) injection, 2 mg/kg) DPD (dihydropyrimidine dehydrogenase)-deficient mouse model [3]
Doses: 2 g/kg
Route of Administration: po (oral gavage), every 8 hrs (hrs (hours)) Once, 15 times in total.
Experimental Results: Starting 4 hrs (hrs (hours)) after 5-FU, the survival rate increased to 100%, and starting within 24 hrs (hrs (hours)), the survival rate increased to 80%. Survival rates improved to 40%, 50%, 20%, 30% and 0% in groups initiated within 48, 72, 96, 120 and 144 hrs (hrs (hours)), respectively.

Absorption, Distribution and Excretion
Maximum concentrations of uridine in plasma following oral administration are generally achieved within 2 to 3 hours.
Uridine can be excreted via the kidneys, but is also metabolized by normal pyrimidine catabolic pathways present in most tissues.
Circulating uridine is taken up into mammalian cells via specific nucleoside transporters, and also crosses the blood brain barrier.

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

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Biological Half-Life
2 to 2.5 hours

[1]. Ma WW, et al. Emergency use of uridine triacetate for the prevention and treatment of life-threatening 5-fluorouracil and capecitabine toxicity. Cancer. 2017 Jan 1;123(2):345-356.
[2]. Cada DJ, et al. Uridine Triacetate. Hosp Pharm. 2016 Jun;51(6):484-8.
[3]. Rolando A G Garcia, et al. Prompt treatment with uridine triacetate improves survival and reduces toxicity due to fluorouracil and capecitabine overdose or dihydropyrimidine dehydrogenase deficiency. Toxicol Appl Pharmacol. 2018 Aug 15;353:67-73.
[4]. Siennah R Miller, et al. Predicting Drug Interactions with Human Equilibrative Nucleoside Transporters 1 and 2 Using Functional Knockout Cell Lines and Bayesian Modeling. Mol Pharmacol. 2021 Feb;99(2):147-162.

Uridine triacetate is an acetate ester that is uracil in which the three hydroxy hydrogens are replaced by acetate group. A prodrug for uridine, it is used for the treatment of hereditary orotic aciduria and for management of fluorouracil toxicity. It has a role as a prodrug, a neuroprotective agent and an orphan drug. It is a member of uridines and an acetate ester.
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. 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.
Uridine Triacetate is a synthetic uridine pro-drug that is converted to uridine in vivo. Uridine, a pyrimidine nucleotide, has been used in a variety of diseases including depressive disorders and inherited myopathies. (NCI04)

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Drug 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.
FDA Label

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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 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.

C15H18N2O9

370.3114

370.101

4105-38-8

20058

White to off-white solid powder

1.4±0.1 g/cm3

124-134ºC

1.552

-0.11

1

9

8

26

660

4

O1[C@]([H])(C([H])([C@]([H])([C@@]1([H])C([H])([H])OC(C([H])([H])[H])=O)OC(C([H])([H])[H])=O)OC(C([H])([H])[H])=O)N1C([H])=C([H])C(N([H])C1=O)=O

AUFUWRKPQLGTGF-FMKGYKFTSA-N

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

[(2R,3R,4R,5R)-3,4-diacetyloxy-5-(2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl acetate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~270.04 mM)
H2O : ~10 mg/mL (~27.00 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.75 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.75 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.75 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 24 mg/mL (64.81 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)