Gimeracil   中文名称: 吉莫斯特

吉美嘧啶降低了新阳性克隆的频率。此外，与 G0/G1 期细胞相比，它还提高了 S 期细胞的敏感性 [1]。 Gimeracil 抑制 HR 介导的 DNA 修复途径，这可能会提高放射治疗的有效性 [1]。虽然用 gigeracil 预处理增加了 Nbs1、Mre11、Rad50 和 FancD2 病灶的数量，但它显着减少了辐射诱导的 Rad51 和 RPA 病灶的发展 [2]。

Gimeracil（口服，2.5–25 mg/kg）可以防止 X 射线造成的肿瘤 DNA 损伤快速愈合 [3]。

细胞活力测定[1]
细胞类型：DLD-1、HeLa 和 LC-11 细胞系。
测试浓度：1 mM。
孵化时间：48小时。
实验结果：抑制辐射引起的 DNA 双链断裂的修复。未照射细胞中 24 小时时未增加 c-H2AX 焦点残留。

Animal/Disease Models: Nude mice (Lu-99, LC-11, KB/C3 and PAN-4 tumors were xenografted)[3].
Doses: 2.5-25 mg/kg.
Route of Administration: Orally.
Experimental Results: demonstrated anti-tumor activity.

Absorption, Distribution and Excretion
Mean 5-FU maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) values were approximately 3-fold higher after Teysuno administration than after administration of tegafur alone, despite a 16-fold lower Teysuno dose (50 mg of tegafur) compared to tegafur alone (800 mg), and are attributed to inhibition of DPD by gimeracil. Maximum plasma uracil concentration was observed at 4 hours, with a return to baseline levels within approximately 48 hours after dosing, indicating the reversibility of the DPD inhibition by gimeracil. After administration of a single dose of 50 mg Teysuno (expressed as tegafur content), median Tmax for Teysuno components tegafur, gimeracil, and oteracil was 0.5, 1.0, and 2.0 hours, respectively.
Following a single dose of Teysuno, approximately 3.8% to 4.2% of administered tegafur, 65% to 72% of administered gimeracil, and 3.5% to 3.9% of administered oteracil were excreted unchanged in the urine.
Although no intravenous data are available for Teysuno in humans, the volume of distribution could be roughly estimated from the apparent volume of distribution and urinary excretion data as 16 l/m2, 17 l/m2, and 23 l/m2 for tegafur, gimeracil and oteracil, respectively.

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Biological Half-Life
Following a single dose of Teysuno, T1/2 values ranged from 6.7 to 11.3 hours for tegafur, from 3.1 to 4.1 hours for gimeracil, and from 1.8 to 9.5 hours for oteracil.

Protein Binding
Oteracil, gimeracil, 5-FU, and tegafur are 8.4%, 32.2%, 18.4%, and 52.3% protein bound, respectively.

[1]. Gimeracil sensitizes cells to radiation via inhibition of homologous recombination. Radiother Oncol. 2010 Aug;96(2):259-66.

[2]. Gimeracil, an inhibitor of dihydropyrimidine dehydrogenase, inhibits the early step in homologous recombination. Cancer Sci. 2011 Sep;102(9):1712-6.

[3]. Gimeracil, a component of S-1, may enhance the antitumor activity of X-ray irradiation in human cancer xenograft models in vivo. Oncol Rep. 2010 Nov;24(5):1307-13.

Gimeracil is an organic molecular entity.
Gimeracil is an adjunct to antineoplastic therapy, used to increase the concentration and effect of the main active componets within chemotherapy regimens. Approved by the European Medicines Agency (EMA) in March 2011, Gimeracil is available in combination with [DB03209] and [DB09256] within the commercially available product "Teysuno". The main active ingredient in Teysuno is [DB09256], a pro-drug of [DB00544] (5-FU), which is a cytotoxic anti-metabolite drug that acts on rapidly dividing cancer cells. By mimicking a class of compounds called "pyrimidines" that are essential components of RNA and DNA, 5-FU is able to insert itself into strands of DNA and RNA, thereby halting the replication process necessary for continued cancer growth. Gimeracil's main role within Teysuno is to prevent the breakdown of [DB00544] (5-FU), which helps to maintin high enough concentrations for sustained effect against cancer cells. It functions by reversibly and selectively blocking the enzyme dihydropyrimidine dehydrogenase (DPD), which is involved in the degradation of 5-FU. This allows higher concentrations of 5-FU to be achieved with a lower dose of tegafur, thereby also reducing toxic side effects.
Gimeracil is a pyridine derivative with antitumor activity. Gimeracil enhances the antitumor activity of fluoropyrimidines by competitively and reversibly inhibiting the enzyme dihydropyrimidine dehydrogenase causing decreased degradation of the fluoropyrimidines.

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Drug Indication
Gimeracil is used as an adjunct to antineoplastic therapy. When used within the product Teysuno, gimeracil is indicated for the treatment of adults with advanced gastric (stomach) cancer when given in combination with cisplatin.

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Mechanism of Action
Gimeracil's main role within Teysuno is to prevent the breakdown of [DB00544] (5-FU), which helps to maintin high enough concentrations for sustained effect against cancer cells. It functions by reversibly blocking the enzyme dihydropyrimidine dehydrogenase (DPD), which is involved in the degradation of 5-FU.

C5H4CLNO2

145.54

144.993

103766-25-2

54679224

White to light brown solid powder

1.6±0.1 g/cm3

524.2±45.0 °C at 760 mmHg

274 °C

270.8±28.7 °C

0.0±1.4 mmHg at 25°C

1.641

-1.5

53.09

2

2

0

9

207

0

ZPLQIPFOCGIIHV-UHFFFAOYSA-N

InChI=1S/C5H4ClNO2/c6-3-2-7-5(9)1-4(3)8/h1-2H,(H2,7,8,9)

5-chloro-2-hydroxypyridin-4(1H)-one

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (17.18 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 (17.18 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 (17.18 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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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。