Eniluracil
(Synonyms: 5-乙炔基尿嘧啶,5-Ethynyluracil; GW776C85) 目录号 : GC35992
An irreversible DPD inhibitor
Cas No.:59989-18-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Eniluracil is an irreversible inhibitor of dihydropyrimidine dehydrogenase (DPD; Ki = 1.6 ?M), the rate-determining enzyme in the catabolism of pyrimidines, including 5-fluorouracil .1,2 It inhibits liver DPD and elevates plasma pyrimidine levels in rats (ED50s = 1.8 and 10 ?g/kg, respectively).2 Eniluracil (2 mg/kg) potentiates the antitumor effects of 5-fluorouracil in MC-38 murine colon carcinoma and MOPC 315 murine myeloma models.
1.Porter, D.J., Chestnut, W.G., Merrill, B.M., et al.Mechanism-based inactivation of dihydropyrimidine dehydrogenase by 5-ethynyluracilJ. Biol. Chem.267(8)5236-5242(1992) 2.Baccanari, D.P., Davis, S.T., Knick, V.C., et al.5-Ethynyluracil (776C85): A potent modulator of the pharmacokinetics and antitumor efficacy of 5-fluorouracilProc. Natl. Acad. Sci. USA90(23)11064-11068(1993)
| Cas No. | 59989-18-3 | SDF | |
| 别名 | 5-乙炔基尿嘧啶,5-Ethynyluracil; GW776C85 | ||
| Canonical SMILES | O=C(N1)NC=C(C#C)C1=O | ||
| 分子式 | C6H4N2O2 | 分子量 | 136.11 |
| 溶解度 | DMSO: 62.5 mg/mL (459.19 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 7.347 mL | 36.735 mL | 73.47 mL |
| 5 mM | 1.4694 mL | 7.347 mL | 14.694 mL |
| 10 mM | 0.7347 mL | 3.6735 mL | 7.347 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Eniluracil: an irreversible inhibitor of dihydropyrimidine dehydrogenase
Expert Opin Investig Drugs 2000 Jul;9(7):1635-49.PMID:11060767DOI:10.1517/13543784.9.7.1635.
One of the most widely used drugs in cancer chemotherapy is 5-fluorouracil (5-FU). 5-FU is optimally delivered via continuous iv. infusion, which is both cumbersome and expensive. Prolonged oral dosing of 5-FU could mimic continuous infusion with less inconvenience and cost. However, oral administration of 5-FU has been hampered by incomplete and erratic bioavailability due to substantial variability in the activity of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in 5-FU catabolism. Eniluracil (ethynyluracil, GlaxoWellcome, USA), a uracil analogue, which irreversibly inhibits DPD, increases the oral bioavailability of 5-FU to 100%, facilitating uniform absorption and predictable toxicity. Cytotoxicity is enhanced one- to five-fold in cell lines treated with Eniluracil plus 5-FU compared with 5-FU alone. Though Eniluracil is neither toxic nor active as a single agent in animals, it improves the antitumour efficacy and therapeutic index of 5-FU. In Phase I trials, Eniluracil markedly reduced the maximum tolerated dose of oral 5-FU, increased the half-life 20-fold and decreased the clearance 22-fold. DPD is completely inactivated within 1 h of Eniluracil administration. Two dosing schedules have been evaluated in combination with oral 5-FU: a 5-day schedule every 28 days and a 28-day schedule every 35 days. The dose-limiting toxicity on the first schedule is myelosuppression with diarrhoea being dose-limiting on the 28-day schedule. Phase II trials employing the 28-day schedule have been completed in cancers of the colon, breast, liver and pancreas. Phase III trials in colorectal and pancreatic carcinoma have been completed and await analysis. Eniluracil is a promising drug, which permits reliable and safe administration of oral 5-FU and has the potential to overcome 5-FU resistance mediated by overexpression of DPD.
Pharmacology of fluorinated pyrimidines: Eniluracil
Invest New Drugs 2000 Nov;18(4):373-81.PMID:11081573DOI:10.1023/a:1006453500629.
The pharmacological inactivation of dihydropyrimidine dehydrogenase (DPD) represents one strategy to improve 5-FU therapy, which historically has been associated with unpredictable pharmacological behavior and toxicity. This is principally due to high interpatient differences in the activity of DPD, the enzyme that mediates the initial and rate-limiting step in 5-FU catabolism. By inactivating DPD and suppressing the catabolism of 5-FU, Eniluracil has dramatically altered the pharmacological profile of 5-FU. The maximum tolerated dose of oral 5-FU given with oral Eniluracil (1.0 to 25 mg/m2) is substantially lower than conventional 5-FU doses. In the presence of Eniluracil, bioavailability of 5-FU has increased to approximately 100%, the half-life is prolonged to 4 to 6 hours, and systemic clearance is reduced > 20-fold to values comparable the glomerular filtration rate (46 to 58 mL/min/m2). Renal excretion (approximately 45% to 75%), instead of DPD-related catabolism, is the principal route of elimination of oral 5-FU given with Eniluracil. Chronic daily administration of oral 5-FU 1.0 mg/m2 twice daily with Eniluracil 20 mg twice daily produces 5-FU steady-state concentrations (8-38 ng/mL) similar to those achieved with protracted intravenous administration on clinically relevant dose-schedules. On a daily x 5 regimen, higher 5-FU AUC values are related to neutropenia, whereas elevated 5-FU AUC and steady-state concentrations are related to diarrhea when oral 5-FU is given daily with Eniluracil on a chronic schedule. The pharmacokinetic behavior of oral Eniluracil is similar to that for oral 5-FU. Administration of Eniluracil 10 to 20 mg twice daily completely inactivates DPD activity both in peripheral blood mononuclear cells and in colorectal tumor tissue, and prolonged inhibition of DPD after discontinuation of Eniluracil treatment has been noted. In the presence of Eniluracil, oral administration of 5-FU is feasible and variation in 5-FU exposure is reduced, with the anticipation of further reduction in variation as dosing guidelines based on renal function are formulated.
Clinical development of Eniluracil: current status
Oncology (Williston Park) 1998 Oct;12(10 Suppl 7):52-6.PMID:9830627doi
Eniluracil is a potent inactivator of dihydropyrimidine dehydrogenase (DPD), which is the first enzyme in the degradative pathway of systemically administered 5-fluorouracil (5-FU). Two completely oral regimens of Eniluracil plus 5-FU are being evaluated in clinical trials: (1) a chronic schedule with both agents administered BID in a 10:1 ratio for 28 days of a 5-week course, and (2) a 5-day schedule of Eniluracil once daily on days 1 through 7 and 5-FU once daily on days 2 through 6. The clinical development of Eniluracil is being pursued in several tumor types, including colorectal cancer, breast cancer, and pancreatic cancer. Response rates achieved in a phase II study of the chronic schedule of oral Eniluracil/5-FU in patients with colorectal cancer compare favorably with those obtained in trials of intravenous 5-FU and leucovorin, while results from other trials are awaited. Safety analysis for the 28-day schedule has revealed a low incidence of severe toxicities, particularly as compared with standard 5-FU regimens.
Preclinical development of Eniluracil: enhancing the therapeutic index and dosing convenience of 5-fluorouracil
Invest New Drugs 2000 Nov;18(4):365-71.PMID:11081572DOI:10.1023/a:1006401432488.
Eniluracil (5-ethynyluracil, GW 776, 776C85) is being developed as a novel modulator of 5-fluorouracil (5-FU) for the treatment of cancer. Eniluracil is an effective mechanism-based inactivator of dihydropyrimidine dehydrogenase (DPD), the first enzyme in the catabolic pathway of 5-FU. By temporarily eliminating this prevalent enzyme, Eniluracil provides predictable dosing of 5-FU and enables oral administration of 5-FU to replace intravenous bolus and continuously infused dosing. New DPD is synthesized with a half-life of 2.6 days. It also eliminates the formation of problematic 5-FU catabolites. Most importantly, in laboratory animals, Eniluracil increases the therapeutic index and absolute efficacy of 5-FU. Accompanying reports in this journal indicate that Eniluracil has promising clinical potential.
Eniluracil plus 5-fluorouracil and leucovorin: treatment for metastatic breast cancer patients in whom capecitabine treatment rapidly failed
Clin Breast Cancer 2014 Feb;14(1):26-30.PMID:24183612DOI:10.1016/j.clbc.2013.08.018.
Background: As part of a comparative phase II study of Eniluracil/5-FU/Lv vs. capecitabine (Xeloda), an oral 5-FU prodrug for MBC, patients with rapid PD during capecitabine therapy crossed over to take Eniluracil/5-FU/Lv. Patients and methods: Ten evaluable patients with radiologically documented PD within 70 days of capecitabine treatment were treated with a modified oral weekly Eniluracil/5-FU/Lv regimen. Results: After switching to Eniluracil/5-FU/Lv, 3 (30%) patients had PR. Six (60%) had SD, producing a total of 90% with PR or SD. The median PFS was 140 days (vs. 42.5 days for capecitabine). Four (40%) patients had > 7 months PFS. Eniluracil/5-FU/Lv was well tolerated with mild to moderate diarrhea and nausea as the most common side effects. Conclusion: These positive efficacy and safety results encourage a larger study in patients with rapid PD during capecitabine treatment. Eniluracil/5-FU/Lv might enable these patients to continue with oral 5-FU rather than switching to the generally less well tolerated intravenous microtubule-interfering agents. In addition, the Eniluracil/5-FU/Lv regimen might also provide any overall survival contribution of 5-FU that, for pharmacokinetic reasons, was not provided by capecitabine and would not be provided if these patients progressed directly to the other approved treatments.