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

The abilities of the members of a homologous series of 1-alkylaminocarbonyl-5-fluorouracil (5-FU) prodrugs to deliver 5-FU, 1, through hairless mouse skin from isopropyl myristate (IPM) have been evaluated (alkyl = CH3 to C8H17). The most effective member of the series was the propyl derivative which also exhibited the highest water (buffer) solubility of any of the prodrugs. Generally the members of the series were not very effective, with a maximum enhancement of only 3-times the rate of delivery of 5-FU by itself. All of the prodrugs were more lipid soluble than 5-FU and the prodrugs exhibited partition coefficient values that were comparable to other, more effective types of N-acyl prodrugs. The lack of effectiveness appears to be due to the lower buffer solubilities exhibited by these 1-alkylaminocarbonyl-5-FU prodrugs compared to the other types of N-acyl prodrugs. The lower buffer solubility, in turn, appears to be due to the fact that the hydrogen bonding donor ability of the N-alkylaminocarbonyl type of prodrug is not reduced compared to the other types of N-acyl prodrugs. Some differences in the literature for the physicochemical properties of the N-alkylaminocarbonyl series of prodrugs have been reconciled by an examination of their thermal properties.