Topical delivery of 5-fluorouracil (5-Fu) by 3-alkylcarbonyl-5-Fu prodrugs.
The solubilities in isopropyl myristate (SIPM) and pH 4.0 buffer (SAQ) and the partition coefficients between IPM and pH 4.0 buffer (KIPM: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 the 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 species through hairless mouse skin from IPM suspensions (Ji) were also measured. The 3-propionyl derivative 3, which exhibited the highest SAQ in the series, gave the highest Ji value. The SIPM, SAQ and molecular weights (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 logJi using the transformed Potts-Guy equation. Although the series of 3-AC-5-FU prodrugs was generally quite effective at increasing Ji (2-20 times), the best 3-AC-5-FU prodrug was not as effective as the best 1-alkylcarbonyl-5-FU prodrug (1-AC-5-FU) at increasing Ji and the ability of the 3-AC-5-FU prodrugs to increase the concentration of total 5-FU species in the skin was 2-5 times 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.
Beall
H D
HD
Department of Pharmaceutical Sciences, The University of Montana, 32 Campus Drive #1552, Missoula, Montana 59812-1552, USA.
Sloan
K B
KB
D000287:Administration, Topical; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004058:Diffusion; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D051379:Mice; D008812:Mice, Hairless; D010539:Permeability; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012867:Skin / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; C082012:3-acetyl-5-fluorouracil; D005472:Fluorouracil