Tegafur is a bioactivator of the hepatic microsomal cytochrome P450 enzyme, 5-FU. The active metabolites 5-fluorodeoxyuridine-monophosphate (FdUMP) and 5-fluorouridine-triphosphate (FUTP), which are embedded in cells and inhibit thymidylate synthase, are produced intracellularly from 5-FU mask. This leads to decreased thymidine synthesis, decreased DNA synthesis, disruption of RNA function, and toxicity to tumor cells.

Absorption, Distribution and Excretion
The pharmacokinetic properties of tegafur are dose-proportional. Tegafur is rapidly and adequately absorbed into the systemic circulation, reaching peak plasma concentrations within 1 to 2 hours after administration. Approximately 20% of tegafur is excreted unchanged in the urine after oral administration. Based on the apparent volume of distribution and urinary excretion data, the volume of distribution of tegafur is calculated to be 16 L/m². Pharmacokinetic data are currently unavailable. Metabolism/Metabolites The hepatic CYP2A6 enzyme is the main enzyme mediating the 5-hydroxylation of tegafur to 5'-hydroxytegafur. This metabolite is unstable and spontaneously degrades to 5-fluorouracil (5-FU), an active antitumor drug with pharmacological effects against tumors. 5-Fluorouracil (5-FU) is primarily metabolized by the hepatic enzyme dihydropyrimidine dehydrogenase (DPD). Known metabolites of tegafur include 5-fluorouracil.

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Biological Half-Life
The elimination half-life of tegafur is approximately 11 hours.

Protein Binding
Tegafur had a binding rate of 52.3% to serum proteins, while 5-fluorouracil had a binding rate of 18.4% to serum proteins.

[1]. Association of right-sided tumors with high thymidine phosphorylase gene expression levels and the response to oral uracil and tegafur/leucovorin chemotherapy among patients with colorectal cancer. Cancer Chemotherapy and Pharmacology. 2012, 70 (2): 285-291.

[2]. Engineering of an antitumor (core/shell) magnetic nanoformulation based on the chemotherapy agent ftorafur. Colloids and Surfaces A: Physicochemical and Engineering Aspects. 2011,384(1-3): 157-163.

[3]. A phase 2 study of a fixed combination of uracil and ftorafur (UFT) and leucovorin given orally in a 3-times-daily regimen to treat patients with recurrent metastatic breast cancer. Cancer. 2010, 116(6): 1440-1445.

[4]. Pharmacokinetics of 5-Fluorouracil in Elderly Japanese Patients with Cancer Treated with S-1 (a Combination of Tegafur and Dihydropyrimidine Dehydrogenase Inhibitor 5-Chloro-2,4-dihydroxypyridine). Drug Metab Dispos. 2009 Jul;37(7):1375-7. doi: 10.1124/dmd.109.027052. Epub 2009 Apr 23.

[5]. Tegafur-uracil.

Tegafur is an organohalogen compound belonging to the pyrimidine class of compounds. Tegafur (International Nonproprietary Name, Biologics Name, US Generic Name) is a prodrug of 5-fluorouracil (5-FU), an anti-tumor drug used to treat various cancers, such as advanced gastric and colorectal cancer. It is a pyrimidine analogue that can be used in combination with 5-FU as an active chemotherapeutic agent, for example, in combination with 5-FU (DB09257) and 5-FU (DB03209), or in combination with 5-FU (DB00544), for example, in combination with 5-FU (DB09327). Tegafur is often used in combination with other drugs that enhance the bioavailability of 5-FU by blocking the enzymes responsible for its degradation, or limit its toxicity by ensuring high concentrations of 5-FU at lower doses of tegafur. 5-Fluorouracil (5-FU), after conversion and bioactivation, exerts its anticancer effect by inhibiting thymidine synthase (TS), which is involved in DNA synthesis in the pyrimidine pathway. 5-FU is listed in the World Health Organization's Essential Medicines List. Tegafur, a homologue of the antimetabolite fluorouracil, possesses antitumor activity. Tegafur is a prodrug that is gradually converted to fluorouracil in the liver by cytochrome P-450 enzymes. Subsequently, 5-FU is metabolized in tumor cells and normal cells into two active metabolites: 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). FdUMP inhibits DNA synthesis and cell division by inhibiting thymidine synthase and reducing the production of normal thymidine, while FUTP inhibits RNA and protein synthesis by competing with uridine triphosphate. (NCI04) A homologue of fluorouracil, it has similar antitumor effects. It is particularly recommended for the treatment of breast cancer.

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Drug Indications
Usually used in combination with other biochemical modulatory drugs for the treatment of cancer. Used in combination with [DB00515] for the treatment of advanced gastric cancer in adults. Used in combination with [DB03419] and leucovorin calcium for first-line treatment of metastatic colorectal cancer.

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Mechanism of Action
The conversion of 2'-deoxyuridine monophosphate (dUMP) to 2'-deoxythymidine monophosphate (dTMP) is a key step driving intracellular DNA and purine synthesis. Thymidine synthase catalyzes the conversion of dUMP to dTMP, which is a precursor to thymidine triphosphate (TTP), one of the four deoxynucleotides required for DNA synthesis. After entering the body, tegafur is converted into the active antitumor metabolite fluorouracil (5-FU). In tumor cells, 5-FU is phosphorylated to form active metabolites, including 5-fluorodeoxyuridine monophosphate (FdUMP). FdUMP and reduced folic acid bind to thymidine synthase to form a ternary complex, thereby inhibiting DNA synthesis. Furthermore, 5-fluorouridine triphosphate (FUTP) can be incorporated into RNA, leading to RNA dysfunction.

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Pharmacodynamics
Tegafur is a pyrimidine analogue antitumor drug. It interferes with the synthesis of 2'-deoxythymidine monophosphate (DTMP) in the pyrimidine metabolic pathway, thereby inhibiting DNA synthesis. A phase III clinical trial evaluating the efficacy of S-1 (tegafur/gammidine/oteracis) in patients with advanced or recurrent gastric cancer showed that this regimen, when combined with cisplatin, had a high objective response rate and significantly prolonged overall survival and progression-free survival. A meta-analysis showed that triple therapy consisting of tegafur, gimeracil, and oteracis prolonged the survival of patients with advanced gastric cancer and was well-tolerated. Tegafur and its active metabolites are potent myelosuppressants.

C8H9FN2O3

200.17

200.059

17902-23-7

5386

White to off-white solid powder

1.5±0.1 g/cm3

171-173 °C(lit.)

1.557

-0.77

1

4

1

14

316

0

WFWLQNSHRPWKFK-UHFFFAOYSA-N

InChI=1S/C8H9FN2O3/c9-5-4-11(6-2-1-3-14-6)8(13)10-7(5)12/h4,6H,1-3H2,(H,10,12,13)

5-fluoro-1-(oxolan-2-yl)pyrimidine-2,4-dione

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 48 mg/mL (~239.80 mM)
H2O : ≥ 20 mg/mL (~99.92 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (12.49 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 (12.49 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 (12.49 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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 (Please use freshly prepared in vivo formulations for optimal results.)