Topical delivery of 5-fluorouracil (5-FU) by 3-alkylcarbonyl-5-FU prodrugs

The solubilities in isopropyl myristate (S-IPM) and pH 4.0 buffer (S-AQ) an d the partition coefficients between IPM and pH 4.0 buffer (K-IPM:AQ) have been measured for a series of 3-alkylcarbonyl-5-fluorouracil prodrugs (3-AC -5-FU). The 3-AC-5-FU prodrugs were all 100 times more soluble in IPM and t he first two members of the series were also more soluble in pH 4.0 buffer than 5-FU. The abilities of the 3-AC-5-FU prodrugs to deliver total 5-FU sp ecies through hairless mouse skin from IPM suspensions (J(i)) were also mea sured. The 3-propionyl derivative 3, which exhibited the highest S-AQ in th e series, gave the highest J(i) value. The S-IPM, S-AQ and molecular weight s (mw) of the 3-AC-5-FU series correctly predicted the rank order and very closely (0.10 log units) predicted the absolute values for log J(i) using t he transformed Potts-Guy equation. Although the series of 3-AC-5-FU prodrug s was generally quite effective at increasing J(i) (2-20 times), the best 3 -AC-5-FU prodrug was not as effective as the best 1-alkylcarbonyl-5-FU prod rug (1-AC-5-FU) at increasing J(i) and the ability of the 3-AC-5-FU prodrug s to increase the concentration of total 5-FU species in the skin was 2-5 t imes less than the 1-AC-5-FU prodrugs. Thus, the 1-AC-5-FU prodrugs remain as the best prodrugs with which to enhance the topical delivery of 5-FU. (C ) 2001 Elsevier Science B.V. All rights reserved.