Uridine triacetate is a prodrug of uridine, which is the active metabolite. Uridine is a naturally occurring nucleoside that plays a critical role in pyrimidine metabolism and is a precursor for RNA synthesis. In hereditary orotic aciduria, a deficiency of uridine monophosphate synthase (UMPS) leads to impaired pyrimidine synthesis. Uridine supplementation bypasses this metabolic block by providing an exogenous source of uridine. In fluorouracil or capecitabine toxicity, uridine competes with fluorouracil metabolites, reducing their incorporation into RNA and DNA and thereby decreasing toxicity.

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].
In vitro, uridine triacetate is a prodrug that is converted to uridine by deacetylation. The released uridine is taken up by cells and incorporated into pyrimidine metabolism. Its activity is characterized by its ability to increase intracellular uridine levels and support RNA synthesis. Uridine triacetate is more lipid-soluble than uridine and resistant to degradation by uridine phosphorylase, which enhances its oral bioavailability.

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].
In vivo, uridine triacetate is effective in treating hereditary orotic aciduria and in managing fluorouracil or capecitabine overdose or toxicity. 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. The compound is FDA-approved for these indications.

In vitro enzyme/receptor binding (non-cell) assays are not applicable to uridine triacetate as it is a prodrug that does not directly interact with enzymes or receptors. Its activity is mediated by its conversion to uridine, which is a natural metabolite.

In vitro cell-based experiments for uridine triacetate involve treating cells with the compound and measuring intracellular uridine levels. Cells are treated with uridine triacetate at varying concentrations, and uridine uptake and incorporation into RNA are assessed using radiolabeled or mass spectrometry-based methods. The compound's ability to rescue cells from fluorouracil toxicity is evaluated in cell-based assays.

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.
In vivo animal experiments for uridine triacetate are performed in animal models of fluorouracil toxicity and hereditary orotic aciduria. Uridine triacetate is administered orally, and survival, toxicity markers, and metabolic parameters are assessed. Clinical studies in humans have also been conducted to support FDA approval.

Absorption, Distribution and Excretion
Following oral administration, the maximum plasma concentration of uridine is typically reached within 2 to 3 hours. Urate is excreted by the kidneys and is also metabolized in most tissues via normal pyrimidine catabolism. Circulating uridine is taken up by mammalian cells via specific nucleoside transporters and can cross the blood-brain barrier. Metabolism/Metabolites Following oral administration, uridine triacetate is deacetylated in vivo by nonspecific esterases, generating uridine which enters the bloodstream. Biological Half-Life 2 to 2.5 hours
Uridine triacetate is orally bioavailable with good absorption in the gut. Following oral administration, it is efficiently absorbed and swiftly deacetylated to release uridine. The released uridine enters the bloodstream and is taken up by cells. Detailed pharmacokinetic parameters, including Cmax, Tmax, AUC, and half-life, are available from clinical studies.

Preclinical and clinical toxicology studies have been conducted to evaluate the safety profile of uridine triacetate. The compound is well-tolerated at therapeutic doses. Uridine triacetate is FDA-approved for the treatment of hereditary orotic aciduria and for the emergency treatment of fluorouracil or capecitabine overdose or toxicity, indicating a favorable safety profile for these indications.

[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, a derivative of uracil, in which three hydroxyl hydrogens are replaced by acetic acid groups. As a prodrug of uridine, it is used to treat hereditary orotic aciduria and to control fluorouracil poisoning. It has multiple functions, including as a prodrug, neuroprotective agent, and orphan drug. It belongs to the uridine class of compounds and is an acetate ester. Uridine triacetate, formerly known as Vestouridine, is an orally effective prodrug of the natural nucleoside uridine. It is used to treat hereditary orotic aciduria (trade name: Xuriden) or for emergency treatment of fluorouracil or capecitabine overdose or poisoning (trade name: Vistogard). It is administered in the form of uridine triacetate because this form increases the amount of uridine entering the systemic circulation by 4 to 6 times compared to an equimolar dose of uridine. When used to treat or prevent fluorouracil and other antimetabolite-related toxicities, the mechanism of action of uridine triacetate is to compete with 5-fluorouracil (5-FU) metabolites for incorporation into the genetic material of non-cancerous cells. It reduces the 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, which is essential for thymidine synthesis as well as DNA replication and repair; FUTP is incorporated into RNA, leading to RNA chain defects. Therefore, these metabolites can cause a variety of adverse reactions, such as neutropenia, mucositis, diarrhea, and hand-foot syndrome. Like many other antitumor drugs, these side effects limit the dosage of 5-FU, thus affecting therapeutic efficacy. Higher doses of 5-fluorouracil (5-FU) can be administered by pre-administering uridine (in the form of the prodrug uridine triacetate), thereby improving efficacy and reducing toxic side effects. Urinidine triacetate can also be used as a rescue treatment if serious side effects occur within 96 hours of starting treatment. Urinidine triacetate is also used to treat hereditary orotic aciduria, also known as uridine monophosphate synthase deficiency. This rare, congenital, autosomal recessive pyrimidine metabolism disorder is caused by a deficiency in uridine monophosphate synthase (UMPS). UMPS is a bifunctional enzyme that catalyzes the last two steps of the de novo pyrimidine synthesis pathway. Due to UMPS deficiency, patients experience a systemic deficiency of pyrimidine nucleotides, which explains most of the symptoms of the disease. Furthermore, orotic acid produced in the de novo pyrimidine synthesis pathway cannot be converted to uridine monophosphate (UMP) and is excreted in the urine, hence the common name \"orotic aciduria.\" Moreover, orotic acid crystals in the urine can cause obstructive urinary tract infections. When administered as a uridine triacetate prodrug, almost all cells can utilize uridine to synthesize uridine nucleotides, thus compensating for the genetic defect in uridine nucleotide synthesis in patients with hereditary orotic aciduria. When intracellular uridine nucleotide levels return to normal, feedback inhibition reduces the excessive production of orotic acid, thereby decreasing the excretion of orotic acid in the urine. Uridine triacetate is a synthetic uridine prodrug that can be converted to uridine in the body. Urate is a pyrimidine nucleotide that has been used to treat a variety of conditions, including depression and hereditary myopathy. (NCI04)

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Drug Indications
Uridine triacetate is marketed under the brand name Xuriden (FDA approved) for the treatment of hereditary orotic aciduria. Uridine triacetate is marketed under the brand name Vistogard (FDA approved) for the emergency treatment of adult and pediatric patients in the following situations: after an overdose of fluorouracil or capecitabine, regardless of the presence or absence of symptoms; or in the event of an early-onset, serious or life-threatening toxicity affecting the heart or central nervous system, and/or an early-onset, unusually serious adverse reaction (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours after the end of administration of fluorouracil or capecitabine.
FDA Label

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Mechanism of Action
Uridine triacetate is a synthetic uridine prodrug that is converted into uridine in the body. When uridine triacetate is used to treat or prevent toxicities associated with fluorouracil and other antimetabolites, its mechanism of action involves competitive incorporation into the genetic material of non-cancerous cells against 5-fluorouracil (5-FU) metabolites. 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 uridine (in the form of the prodrug uridine triacetate), higher doses of 5-FU can be delivered, thereby improving efficacy and reducing toxic side effects such as neutropenia, mucositis, diarrhea, and hand-foot syndrome. Uridine triacetate is also used as a replacement therapy for hereditary orotic aciduria, also known as uridine monophosphate synthase (UMPS) deficiency. Patients with uracil nucleotide synthase (UMPS) deficiency exhibit a systemic deficiency of pyrimidine nucleotides, which explains most of the symptoms of this disease. Furthermore, orotic acid produced via the de novo pyrimidine synthesis pathway cannot be converted into uracil nucleotides (UMP) and is excreted in the urine, which is why the disease is commonly known as \"orotic aciduria.\" Moreover, orotic acid crystals in the urine can cause obstructive urinary tract infections. When administered in the form of uridine triacetate (a prodrug), almost all cells can utilize uridine to synthesize uracil nucleotides, thereby compensating for the genetic defects in synthesis in patients with hereditary orotic aciduria.
Uridine triacetate is also known as 2',3',5'-Triacetyluridine, Vistonuridine, and PN401. It is FDA-approved under the brand name Xuriden for the treatment of hereditary orotic aciduria. It is also approved for the emergency treatment of fluorouracil or capecitabine overdose or toxicity. As an orally active prodrug of uridine, it provides a valuable therapeutic option for these indications.

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.)