TRANSDERMAL DELIVERY OF 5-FLUOROURACIL (5-FU) BY 1-ALKYLCARBONYL-5-FUPRODRUGS

The members of a series of 1-alkylcarbonyl-5-FU prodrug derivatives ha ve been characterized and evaluated for their abilities to deliver 5-F U 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 w as a correlation with water solubility within the series. Although the ir lipid solubilities and partition coefficient values were greater th an 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 sp ecies through the skin than the corresponding member of the 1-alkyloxy carbonyl series. On the other hand, the 1-alkylcarbonyl series was mor e effective at enhancing the ratio of dermal to transdermal delivery ( D/T delivery ratio) than the 1-alkyloxycarbonyl series, presumably bec ause 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 hydrol ysis of the prodrug after it partitions into the skin is supported. Al though the prodrugs hydrolyzed rapidly in water, they were stable in i sopropyl myristate (IPM) during their application in IPM to highly hyd rated skin. There was also a good correlation of calculated solubility parameters for the prodrugs with their permeability coefficients.