Tegafur-uracil API Manufacturers

General Description:

Tegafur-uracil, identified by CAS number 74578-38-4, is a notable compound with significant therapeutic applications. Tegafur-uracil is an anti-tumor compound containing tegafur (1-(2-tetrahydrofuryl)-5-fluorouracil) and uracil in a molar ratio of 1:4. It was developed as an anti-cancer therapy by Taiho Pharmaceutical Co Ltd. It is approved in different countries but it is not yet approved by the FDA, Health Canada or EMA.

Indications:

This drug is primarily indicated for: Tegafur-uracil is indicated for the first line treatment of metastatic colorectal cancer with concomitant administration of calcium folinate. Colorectal cancer is the third most diagnosed cancer and 30% of the cases can present the metastatic state. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Tegafur-uracil undergoes metabolic processing primarily in: Tegafur is bioactivated to 5-fluorouracil by the liver microsomal cytochrome P450 enzymes, mainly the CYP 2A6. This bioactivation is marked by the presence of C-5' oxidation and C-2' hydrolysis. The 5-fluorouracil is later transformed into its active metabolite 5-fluorodeoxyuridine-monophosphate and 5-fluorouridine-triphosphate. More than 80% of the administered dose is eliminated due to the metabolism of dihydropyridine dehydrogenase. Some other metabolic products include 3'-hydroxy tegafur, 4'-hydroxy tegafur and dihydro tegafur which all of them are significantly less cytotoxic than 5-fluorouracil. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Tegafur-uracil are crucial for its therapeutic efficacy: The absorption into systemic circulation is very rapid and the peak concentration is reached within 1-2 hours. After a single dose of tegafur/uracil of 300 mg/m2/day in three divided doses, tegafur plasma concentration of >1000 ng/ml are maintained throughout the 8-hour dosing interval, whereas uracil concentrations decline rapidly following the peak concentration. The plasma concentration of 5-fluorouracil peaks at 30-60 min after administration with 200 ng/ml and remain detectable for 8-hour dosing interval. There is no significant long-term accumulation of either uracil, tegafur or 5-fluorouracil. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Tegafur-uracil is an important consideration for its dosing schedule: The presence of uracil generates an increase in the half-life of tegafur and it is registered to be of 11 hours. The elimination half-life of uracil is of 20-40 minutes. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Tegafur-uracil exhibits a strong affinity for binding with plasma proteins: The serum binding protein of tegafur is of 52% while the protein binding of uracil is negligible. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Tegafur-uracil from the body primarily occurs through: Less than 20% of the administered dose of tegafur is excreted intact in the urine following the oral administration. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Tegafur-uracil is distributed throughout the body with a volume of distribution of: The volume of distribution of tegafur is reported to be 59 L while the uracil volume of distribution of 474 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Tegafur-uracil is a critical factor in determining its safe and effective dosage: The reported clearance of tegafur when administered in the form of tegafur/uracil ranged from 47 to 175 ml/min. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Tegafur-uracil exerts its therapeutic effects through: The use of the combination of tegafur and uracil allows increasing the oral bioavailability, improving the pharmacokinetic behavior of the delivered 5-fluoruracil and increasing the half-life of tegafur. The effect of this combo drug can ameliorate the usage by reducing the dosage frequency which tends to be uncomfortable for the patients. The effect of tegafur's metabolites results in a decreased thymidine synthesis, DNA synthesis, disrupted RNA function and tumor cell cytotoxicity. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Tegafur-uracil functions by: The generation of this combo was conceived under the reported activation by the transformation of tegafur to 5-fluorouracil. These findings have convened with results that suggested that the degradation of 5-fluorouracil can be depressed by the addition of uracil. Uracil competitively inhibits the catabolic action of dihydropyrimidine dehydrogenase. This combined activity allows a significant increase in blood and tissue 5-fluorouracil levels by inhibiting its first-pass hepatic metabolism. The active metabolites of tegafur inhibit the enzyme thymidylate synthase (5-fluoro-deoxyuridine-monophosphate) and intercalate into RNA (5-fluorouridine-triphosphate). This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Tegafur-uracil belongs to the class of organic compounds known as halopyrimidines. These are aromatic compounds containing a halogen atom linked to a pyrimidine ring. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions, classified under the direct parent group Halopyrimidines. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Diazines class, specifically within the Pyrimidines and pyrimidine derivatives subclass.

Categories:

Tegafur-uracil is categorized under the following therapeutic classes: Cytochrome P-450 CYP2A6 Substrates, Cytochrome P-450 Substrates. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.