TRANSDERMAL DELIVERY OF 5-FLUOROURACIL (5-FU) THROUGH HAIRLESS MOUSE SKIN BY 1-ALKYLOXYCARBONYL-5-FU PRODRUGS - PHYSICOCHEMICAL CHARACTERIZATION OF PRODRUGS AND CORRELATIONS WITH TRANSDERMAL DELIVERY

The members of a series of 1-alkyloxycarbonyl-5-fluorouracil (5-FU) derivatives have been synthesized, characterized, and evaluated for their abilities to deliver total 5-FU species into and through skin. The most effective member of the series at delivering 5-FU through skin (flux) was the ethyl derivative, 3 (25 times as effective as 5-FU), which was also the most water soluble member of the series. There was a good correlation between flux and water solubility for the entire series but none between flux and lipid solubility. 3 was also the most effective (4.9 times as effective as 5-FU) member of the series at delivering 5-FU into the skin (C-s), and there was a good correlation between C-s and flux except for the hexyl derivative, 6. Although the partition coefficients of the first four members of the 1-alkyloxycarbonyl series were less than those of the corresponding members of the l-alkylaminocarbonyl series, which were previously studied, their water solubilities were 5-30 times greater and they were 3-10 times more effective at delivering total 5-FU species through hairless mouse skin. However, the 1-alkyloxycarbonyl derivatives delivered mostly intact prodrug (42-90%) through skin while the l-alkylaminocarbonyl derivatives delivered mostly (> 90%) 5-FU. In spite of this difference, there was a good correlation between permeability coefficients for total 5-FU species delivered and calculated solubility parameters for both series.