テガフル/ウラシル

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 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).

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.