H 5fu

FIGURE 2.22 Bioactivation of 5-FP.

Another prodrug of 5-FU is 5-fluoro-2-pyrimidinone (5-FP), which is activated by hepatic aldehyde oxidase after oral or intravenous administration (Fig. 2.22).

4.4. Modulation of 5-FU activity

Great efforts have been made to modulate the activity of 5-FU, which have focused on (1) decreasing its degradation, (2) enhancing its potency as a TS inhibitor, and (3) increasing 5-FU activation.

4.4.1. Decreased degradation of 5-FU

More than 80% of administered drug is degraded in the liver by dihydropyrimi-dine dehydrogenase (DPD), which reduces the pyrimidine double bond of 5-FU to give dihydrofluorouracil (DHFU).23 This metabolite is inactive because it cannot give the initial Michael addition with the nucleophilic site of the active center in TS (Fig. 2.23).

Two different approaches have been developed to improve the biostability of 5-FU. The first of them consists in the coadministration of a large amount of uracil, which saturates the DPD enzyme because uracil is its natural substrate; for instance, the formulation known as UFT uses a 4:1 combination of uracil and the

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