Tegafur-uracil mixt.

312.25400

312.08699769 g/mol

DTXSID3023635

130.59000

0.28480

467.1ºC at 760 mmHg

236.3ºC

High doses of tegafur are reported to present unique central nervous system toxicity. The oral administration of tegafur has been reported to present toxicity but the usage of the combo product tegafur/uracil have presented higher levels of 5-fluorouracil without the toxic effects or oral tegafur.

The serum binding protein of tegafur is of 52% while the protein binding of uracil is negligible.

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.

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.

Antimetabolites that are useful in cancer chemotherapy. (See all compounds classified as Antimetabolites, Antineoplastic.)

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.|Less than 20% of the administered dose of tegafur is excreted intact in the urine following the oral administration.|The volume of distribution of tegafur is reported to be 59 L while the uracil volume of distribution of 474 L.|The reported clearance of tegafur when administered in the form of tegafur/uracil ranged from 47 to 175 ml/min

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.

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.

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).

1-(2-Tetrahydrofuryl)-5-fluorouracil