5-Fluorouracil tumor-activated prodrug

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... 

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). 

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