Uridine triacetate   中文名称: 2',3',5'-三乙酰尿苷

在过表达 ENT1 和 ENT2 的 HeLa 细胞中，三乙酸尿苷抑制 [3H] 尿苷吸收，IC50 值分别为 228.4 μM 和 28.4 μM [4]。

每 8 小时口服一次尿苷三乙酸酯 (2 g/kg)，总共 15 剂，已被证明可以提高 5-FU 过量小鼠的存活率并降低毒性 [3]。每 8 小时口服一次尿苷三乙酸酯 (2 g/kg)，共 15 剂，已显示可降低 5-FU 毒性并提高 DPD 缺陷小鼠的存活率 [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
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

[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.

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

142.99

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.75 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (6.75 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (6.75 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 24 mg/mL (64.81 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。