thymidine phosphorylase

胸苷磷酸化酶被药物tipiracil抑制。 Tipiracil 通过阻止胸苷磷酸化酶代谢药物来增加三氟尿苷的暴露。一种治疗转移性结直肠癌的全新口服疗法结合了曲氟尿苷和吡拉西[2]。作为胸苷磷酸化酶抑制剂，tipiracil 具有阻止 FTD 降解的首过效应[3]。

将 HeLa 细胞以 500 个细胞/180 μL/孔的密度一式三份接种在 96 孔板中，预培养 24 小时，然后接受 20 μL 每种药物溶液培养 24 或 72 小时。 24 小时处理后，用磷酸盐缓冲盐水 (PBS) 洗涤细胞，然后将细胞添加到不含药物的培养基中，并再孵育 48 小时。 Cell Counting Kit-8 用于评估细胞生长的抑制。 SAS[3] 用于根据吸光度数据确定 50% 抑制浓度 (IC50) 值。

Absorption, Distribution and Excretion
Absorption of tipiracil is suggested to be done by the gastrointestinal tract. Administration of a single 35 mg/m2 dose of TAS-102 containing tipiracil and trifluridine, generates the absoprtion rates of tipiracil of AUC 301 ng h/ml, maximum observed plasma concentration (Cmax) 69 ng/ml and time for maximum observed plasma concentration (Tmax) 3 h. The consumption of a high-fat and high-calorie meal can decrease Cmax and AUC by 40%. A standardized high-fat, high-calorie meal decreased tipiracil Cmax and AUC by approximately 40% in patients with cancer following administration of a single dose of LONSURF 35 mg.
After single oral administration of LONSURF (60 mg) with [14C]-tipiracil hydrochloride, recovered radioactivity was 77% of the dose, which consisted of 27% urinary excretion and 50% fecal excretion. Tipiracil was the major component and 6-HMU was the major metabolite in urine and feces.
Following a single dose of LONSURF (35 mg/m²) in patients with advanced solid tumours, the apparent volume of distribution (Vd/F) for tipiracil hydrochloride was 333 L.
Following a single dose of LONSURF (35 mg/m²) in patients with advanced solid tumours, the oral clearance (CL/F) for tipiracil hydrochloride was 109 L/hr.

---

Metabolism / Metabolites
Tipiracil does not undergo much metabolism upon first pass. It is not metabolized by the liver or hepatocytes, nor by the cytochrome P450 enzymes. The only tipiracil-derived metabolite found in very small quantities in human plasma, urine or faeces is 6-hydroxymethyluracil (6-HMU) which is not unique of tipiracil. This metabolite is though to be formed either by enterobacterial metabolism. In plasma, this two metabolites can be found in a proportion of tipiracil 53.1% and 6-HMU 30.9%.

---

Biological Half-Life
After administration of LONSURF 35 mg/m², the mean elimination and steady-state half-life (t_1/2) of tipiracil was 2.1 hours and 2.4 hours respectively.

Protein Binding
The plasma protein binding of tipiracil is below 8%.

[1]. Thymidine phosphorylase influences [(18)F]fluorothymidine uptake in cancer cells and patients with non-small cell lung cancer. Eur J Nucl Med Mol Imaging. 2014 Jul;41(7):1327-35.

[2]. Lonsurf (Trifluridine plus Tipiracil): A New Oral Treatment Approved for Patients with Metastatic Colorectal Cancer. Am Health Drug Benefits. 2016 Mar;9(Spec Feature):97-100.

[3]. Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models. Oncol Rep. 2014 Dec;32(6):2319-26.

Tipiracil is a member of the class of pyrimidones that is uracil substituted by chloro and (2-iminopyrrolidin-1-yl)methyl groups at positions 5 and 6 respectively. Used (as the hydrochloride salt) in combination with trifluridine, a nucleoside metabolic inhibitor, for treatment of advanced/relapsed unresectable colorectal cancer. It has a role as an antineoplastic agent and an EC 2.4.2.4 (thymidine phosphorylase) inhibitor. It is a pyrimidone, an organochlorine compound, a carboxamidine and a member of pyrrolidines. It is functionally related to a uracil. It is a conjugate base of a tipiracil(1+).
Tipiracil is a thymidine phosphorylase inhibitor. It is used in combination with trifluridine, in a ratio of 1:0.5, to form TAS-102. The main function of Tipiracil in TAS-102 is to increase trifluridine bioavailability by inhibiting its catabolism. TAS-102 is indicated for the treatment of metastatic colorectal cancer which has been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, or with an anti-VEGF or anti-EGFR therapy.
Tipiracil is a Thymidine Phosphorylase Inhibitor. The mechanism of action of tipiracil is as a Thymidine Phosphorylase Inhibitor.

---

Drug Indication
Tipiracil is also available as a combination product with [Trifluridine], which is indicated either alone or in combination with [bevacizumab] for the treatment of adult patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. This combination product is also used for adult patients with metastatic gastric or gastroesophageal junction adenocarcinoma and were previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan and if appropriate, HER2/neu-targeted therapy.
FDA Label

---

Mechanism of Action
Tipiracil is a thymidine phosphorylase inhibitor. Its function prevents the breakdownof the active component of trifluridine, thus increasing the bioavailability of trifluridine and boosting its systemic presence. In addition, it is reported that thymidine phosphorylase is an angiogenic factor usually overexpressed in solid tumors. There is a direct association of thymidine phosphorylase with a poor prognosis; where the tumors with an elevated expression of this enzyme tend to present an increased angiogenesis and ergo, be more malignant. Therefore, it has been suggested that tipiracil presents an aditional function by downregulating tumoral angiogenesis.

---

Pharmacodynamics
Tipiracil prevents trifluridine conversion into 5-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, which is an inactive major metabolite, by inhibiting the enzyme thymidine phosphorylase. Thus, tipiracil is able to increase trifluridine bioavailability. On the other hand, thymidine phsophorylase is a known platelet-derived endothelial cell growth factor and its inhibition generates an indirect antiangiogenic benefit.

C9H11N4O2CL

242.66224

242.057

183204-74-2

Trifluridine/tipiracil hydrochloride mixture;733030-01-8;Tipiracil hydrochloride;183204-72-0

6323266

White to off-white solid

1.7±0.1 g/cm3

245ºC (decomposition)

1.743

-1.37

93.33

3

3

2

16

404

0

O=C1NC(C(Cl)=C(CN2C(CCC2)=N)N1)=O

QQHMKNYGKVVGCZ-UHFFFAOYSA-N

InChI=1S/C9H11ClN4O2/c10-7-5(12-9(16)13-8(7)15)4-14-3-1-2-6(14)11/h11H,1-4H2,(H2,12,13,15,16)

5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]-1H-pyrimidine-2,4-dione

Tipiracil

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)

H2O: ~1 mg/mL (~4.1 mM)
DMSO: <1 mg/mL

配方 1 中的溶解度: 2 mg/mL (8.24 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。 (<60°C).

---

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。