Transdermal delivery of 5-fluorouracil (5-FU) by 1-alkylcarbonyl-5-FU prodrugs

The members of a series of 1-alkylcarbonyl-5-FU prodrug derivatives have been characterized and evaluated for their abilities to deliver 5-FU into and through skin. There was no correlation of lipid solubility or partition coefficient with relative abilities of the members of the 1-alkylcarbonyl series to deliver 5-FU through skin. However, there was a correlation with water solubility within the series. Although their lipid solubilities and partition coefficient values were greater than those of the 1-alkyloxycarbonyl series, only 1-acetyl-5-FU was more soluble in water, and only 1-acetyl-5-FU delivered more total 5-FU species through the skin than the corresponding member of the 1-alkyloxycarbonyl series. On the other hand, the 1-alkylcarbonyl series was more effective at enhancing the ratio of dermal to transdermal delivery (D/T delivery ratio) than the 1-alkyloxycarbonyl series, presumably because of the rapid hydrolysis of the members of the former series once contact with the aqueous domains of the epidermis had been made. Thus, the hypothesis that enhanced D/T delivery ratio requires rapid hydrolysis of the prodrug after it partitions into the skin is supported. Although the prodrugs hydrolyzed rapidly in water, they were stable in isopropyl myristate (IPM) during their application in IPM to highly hydrated skin. There was also a good correlation of calculated solubility parameters for the prodrugs with their permeability coefficients.