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-alkylaminocar bonyl-5-fluorouracil (5-FU) prodrugs to deliver 5-FU, 1, through hairl ess mouse skin from isopropyl myristate (IPM) have been evaluated (alk yl = CH3 to C8H17). The most effective member of the series was the pr opyl derivative which also exhibited the highest water (buffer) solubi lity of any of the prodrugs. Generally the members of the series were not very effective, with a maximum enhancement of only 3-times the rat e of delivery of 5-FU by itself. All of the prodrugs were more lipid s oluble than 5-FU and the prodrugs exhibited partition coefficient valu es that were comparable to other, more effective types of N-acyl prodr ugs. The lack of effectiveness appears to be due to the lower buffer s olubilities exhibited by these 1-alkylaminocarbonyl-5-FU prodrugs comp ared to the other types of N-acyl prodrugs. The lower buffer solubilit y, in turn, appears to be due to the fact that the hydrogen bonding do nor ability of the N-alkylaminocarbonyl type of prodrug is not reduced compared to the other types of N-acyl prodrugs. Some differences in t he literature for the physicochemical properties of the N-alkylaminoca rbonyl series of prodrugs have been reconciled by an examination of th eir thermal properties.