Fluorouracil orally active

Capecitabine (Xeloda ) Orally active prodrug of 5-fluorouracil. Once activated, the mechanism of action is the same. Similar to continuous infusion 5-fluorouracil... 

Flucytosine 4.23) (5-fluorocytosine, Ancobon ) has proved clinically successful as an orally active fungicide for treating such systemic diseases as candidosis and cryptococcal meningitis (Bennett, 1977). Its selectivity depends on the fact that mammals secrete it unchanged (just as they do cytosine), whereas fungi convert it to 5-fluorouracil and then elaborate this to its cytostatic nucleotide. 

Carmofur [61422-45-5], antineoplastic, orally active fluorouracil derivative, 47. Phosgene is employed to prepare the carbamoyl chloride intermediate 44. A different route, using n-hexyl isocyanate 45, has also been applied [39, 40]. 

Turning our attention first to alkyl carbamates of cyclic amides, we find interesting attempts to improve the pharmaceutical and pharmacokinetic properties of 5-fluorouracil (8.152, R = H) [194-196], This antitumor agent, while clinically useful, suffers from poor water solubility, unsatisfactory delivery properties and low tissue selectivity. A variety of prodrug candidates were prepared, in particular the alkyl and aryl carbamates presented in Table 8.12. With the exception of the more-lipophilic derivatives, these compounds exhibited somewhat improved water solubility. More importantly, both rectal and oral bioavailability were markedly improved. The activation... 

Flucytosine is an oral antifungal pro-drug. It has to be enzymatically deaminated by the fungi to the active metabolite, fluorouracil. Fluorouracil inhibits thymidylate synthetase and DNA synthesis. Its indications are treatment of cryptococcal meningitis and serious systemic candidiasis. Resistance develops rapidly, due to altered drug-permeability. For this reason Amphotericin B and flucytosine are often given in combination as they have synergistic effects. 

The fluorine atom can be present in position 5 in uracil derivatives, or in position 1 in that of purine, as in fludarabine, which is used in the treatment of some leukemias (Figure 6.14 cf. Chapter 8). Nucleoside derivatives of fluorouracil (e.g., capecitabine) are prodrugs that allow the oral administration of 5-FU in cancer chemotherapy. The mechanism of action of these nucleosides is detailed in Chapters 7 and 8. Nucleosides having a trifluoromethylated base have been described for example, trifluridine is active on herpesvirus (Figure 6.14). 

The in vivo metabolism of capecitabine (1) to the active tumor cytotoxic substance 5-fluorouracil (5) is now fairly well understood. When capecitabine is administered orally it is delivered to the small intestine, where it is not a substrate for thymidine phosphorylase in intestinal tissue, and so passes through the intestinal mucosa as an intact molecule and into the bloodstream. When 1 reaches the liver, the carbamate moiety is hydrolyzed through the action of carboxylesterase enzymes, liberating 5 -deoxy-5-fluorocytidine (5 -DFCR, 10). DFUR is partially stable in systemic circulation, but eventually diffuses into tumor cell tissue where it is transformed into 5 -deoxy-5-fluorouridine (5 -DFUR, 9) by cytidine deaminase, an enzyme present in high concentrations in various types of human cancers compared to adjacent healthy cells (although it is present in significantly lower levels in the liver). Within the tumor, 5-... 

Capecitabine is an example of a prodrug chemical delivery system that requires a series of enzymatic steps for conversion to the active antitumor drug species. S-fluorouracil (Scheme 5-24). Tumors located in tissues with high levels of the required enzymes. should respond best to treaunent with capecitabine. Esterase activity occurs primarily in the liver, allowing the intact e.ster capecitabine to be the absorbed species following oral administration. The ester hydrolysis product itself shows some specific toxicity towani... 

Folic acid is a nutritional supplement frequently used during periods of deficiency. Folic acid needs increase during chronic diseases, such as malabsorption liver disease, alcoholism, and anticonvulsant or oral contraceptive use. Folic acid supplementation during pregnancy is strongly recommended to prevent neural tube defects to the unborn child. The active form of folic acid, folinic acid, is used in the management of certain medical diseases (e.g., patients taking methotrexate, and 5-fluorouracil). 

A convenient synthesis was reported for l,3-bis(tetrahydro-2-fur-anyl)-5-fluorouracil (Thf2 FU), whose toxicity and antitumor activity were compared with Ftorafur (Thf-FU) and FU. The oral LDc in mice was approximately 3-fold greater than that observed for Thf-FU, ich was much less toxic than FU. Thf -FU slowly hydrolyzed to FU in vivo and showed significant antitumor effects at 0.15-0.45 mmol/kg (p.o.) against Ehrlich and AH-130 carcinomas, sarcoma 180, Yoshida sarcoma and Walker 256 carcinosarcoma. The most active in a series of 1-alkyIcarbamoyl derivatives of FU was the 1-jt-butylcarbamoyl compound, which gave an of... 

Figure 13.44. Metabolic activation of capecitabine (50), a site-selective multistep prodrug of the antitumor drug 5-fluorouracil (5-FU) (53)Following oral absorption, the prodrug is hydrolyzed by liver carboxylesterase to a carbamic acid that spontaneously decarboxylates to 5 -deow-5-fluorocy-tidine (51). The latter is transformed into 5 -deoxy-5-fluorouridine (52) by cytidine deaminase present in the liver and tumors. The third activation step occurs selectively in tumor cells and involves the transformation to 5-FU (53), catalyzed by thymidine phosphorylase (221).

The kinetics of 5-fluorouracil and its metabolites are essentially nonlinear. Therefore it is extremely difficult to build models that would correctly describe the cascade of nonlinear transformations that are observed, starting from drug absorption to its transformation into the active moiety. More recently, capecit-abine has been commercialized. It is a fluor-pyrimidine carbamate available for oral administration. Concentrations of 5-fluorouracil in some tumors are higher than those in the adjacent healthy tissues. The tumor preferential activation of capecitabine to 5-fluorouracil is explained by tissue differences in the activity of cytidine deaminase and thymidine phos-phorylase. It is interesting to note that the last of the three metabolic steps leading to 5-fluorouracil is the formation of 5 -deoxy-5-fluori-dine. Capecitabine is thus a pro-prodrug (176-178). 

Another oral prodrag of Huorouracil, Atofluding (36) is a diacyl derivative of 1. Atofluding has reached Phase HI clinical trials in China [39]. The activation of 36 includes its fast non-enzymatic hydrolysis to 3-o-toluyl-5-Fluorouracil (44) following oral administration 44 is then slowly metabolized to 1 (Scheme 6) [40]. Since the acetyl group of Atofluding is not stable and prone to decompose, impairing quality control for the preparation, a possibility of direct application of 44 was also considered [41]. 

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