Abstract
The kinetics and mechanism of hydrolysis of various 1-, 3- and 1,3-acyloxymethyl derivatives of 5-fluorouracil were studied to assess their potential as prodrugs with the aim of enhancing the delivery characteristics of the parent drug. All the derivatives hydrolyzed to yield 5-fluorouracil in quantitative amounts, passing through an unstable N-hydroxymethyl-5-fluorouracil intermediate. The pH-rate profiles obtained revealed the occurrence of specific acid and base catalysis as well as of a water-catalyzed reaction. The rates of hydrolysis were accelerated markedly in the presence of human plasma or rat liver homogenate, suggesting the utility of the derivatives as prodrugs. The derivatives were all more lipophilic than 5-fluoro-uracil as determined by partition experiments in octanol-aqueous buffer systems but the aqueous solubility was only slightly reduced or, for some derivatives, even greater than that of 5-fluorouracil. This behaviour was attributed to differences in the crystal lattice energy, and relationships between melting points, partition coefficients and water-solubilities for these and 11 other prodrug derivatives of 5-fluoro-uracil were established.
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