Topical delivery of 5-fluorouracil (5-FU) by 3-alkylcarbonyloxymethyl-5-FU prodrugs.
The 3-alkylcarbonyloxymethyl-5-fluorouracil (3-ACOM-5-FU) prodrugs have been characterized by their solubilities in isopropyl myristate (S(IPM)) and partition coefficients between IPM and pH 4.0 buffer (K(IPM:AQ)). Estimated S(AQ) values have been obtained from S(AQ) = S(IPM)/K(IPM:AQ.) The abilities of the prodrugs to deliver total 5-FU species from IPM suspensions through hairless mouse skin (J(i)) have been evaluated in diffusion cell experiments. All of the prodrugs were much more soluble in IPM than 5-FU, and the propionyloxymethyl (C2) member of the series was almost twice as soluble in pH 4.0 buffer. Except for the acetyloxymethyl (C1) member of the series, the 3-ACOM-5-FU prodrugs exhibited greater S(IPM) and S(AQ) values than the corresponding 1-alkylcarbonyloxymethyl (1-ACOM-5-FU) prodrugs. The 3-ACOM-5-FU prodrugs that exhibited greater S(IPM) and S(AQ) values than the 1-ACOM-5-FU prodrugs also exhibited greater J(i) values, except for the C2 member. The C2 member also gave the largest error in predicting J(i) using the transformed Potts-Guy equation. All of the 3-ACOM-5-FU prodrugs delivered more 5-FU as a percentage of J(i) than the 1-ACOM-5-FU prodrugs but were not more effective as a series at targeting dermal as opposed to transdermal delivery.
Roberts
William J
WJ
Department of Medicinal Chemistry, University of Florida, P. O. Box 100485, Gainesville, Florida 32610, USA.
Sloan
Kenneth B
KB
D000279:Administration, Cutaneous; D000818:Animals; D016503:Drug Delivery Systems; D004817:Epidermis / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D051379:Mice; D008812:Mice, Hairless; D009226:Myristates / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D012869:Skin Absorption; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013329:Structure-Activity Relationship; D044366:Transition Temperature
D007166:Immunosuppressive Agents; D009226:Myristates; D011355:Prodrugs; D012997:Solvents; C008205:isopropyl myristate; D005472:Fluorouracil