Topical delivery of 5-fluorouracil (5-FU) by 1,3-bisalkylcarbonyl-5-FU prodrugs.
The solubilities in isopropyl myristate (S(IPM)) and pH 4.0 buffer (S(AQ)) and the partition coefficients between IPM and pH 4.0 buffer (K(IPM:AQ)) have been measured for a series of 1,3-bisalkylcarbonyl-5-fluorouracil prodrugs (1,3-AC-5-FU). The 1,3-AC-5-FU prodrugs were each over 500 times more soluble in IPM, but all members of the series, whose solubilities could be estimated, were much less soluble in pH 4.0 buffer than 5-FU. The abilities of the 1,3-AC-5-FU prodrugs to deliver total 5-FU species through hairless mouse skin from IPM suspensions (J(i)) were also measured. The 1,3-diacetyl derivative 2, which exhibited the highest S(AQ) in the series, gave the highest J(i) value. Although the series of 1,3-AC-5-FU prodrugs was generally effective at increasing J(i) (three to ten times), the best 1,3-AC-5-FU prodrug was not as effective as the best 1- or 3-alkylcarbonyl-5-FU prodrug (1- or 3-AC-5-FU) at increasing J(i) and their ability to increase the concentration of total 5-FU species in the skin was generally less than that of the 1-AC-5-FU prodrugs, but greater than that of the 3-AC-5-FU prodrugs. Thus, the 1-AC-5-FU prodrugs remain the best prodrugs with which to enhance the topical delivery of 5-FU.
Beall
Howard D
HD
Department of Pharmaceutical Sciences, The University of Montana, 32 Campus Drive No. 1552, Missoula, MT 59812-1552, USA.
Sloan
Kenneth B
KB
D000287:Administration, Topical; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051379:Mice; D008812:Mice, Hairless; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012869:Skin Absorption / Q000502:physiology; D012995:Solubility
D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D005472:Fluorouracil