Improved delivery through biological membranes. LXI: Design, synthesis, and evaluation of a lipolol-based intradermal drug targeting system for 5-fluorouracil.
This report describes initial studies with the lipolyl ester of 1-carboxypropylcarbamoyl-FU (LE-CPCFU) which was designed to enhance the dermal delivery of the antitumor agent 5-fluorouracil (FU). The design of LE-CPCFU was based upon our previous observation that sulfur-based chemical drug targeting systems were localized within the skin and improved the delivery of the parent drug to the dermal tissue (Chikhale et al., 1993; Bodor et al., 1982; Bodor and Sloan, 1982). In the in vitro test system that used freshly-excised guinea-pig skin, LE-CPCFU was found to enhance FU delivery to the skin 2- to 5-fold compared to underivatized FU. Neither LE-CPCFU nor its acid metabolite 1-carboxypropylcarbamoyl-FU (CPCFU) could be detected in the skin or receiver during the diffusion experiments even though LE-CPCFU and CPCFU were found to be reasonably stable in aqueous pH 7.4 buffer and during the analytical procedure. FU which was released from LE-CPCFU in the skin subsequently diffused into the receiver. Thus, LE-CPCFU was observed to improve FU delivery to the skin during the initial time period of the study (0-4 hr). This study indicates that LE-CPCFU in the guinea-pig skin was hydrolyzed to form FU in the skin serving as an intradermal drug delivery system for the antitumor agent. Thus, LE-CPCFU could prove to reduce the systemic toxicity of FU by enhancing the local skin concentration and minimizing the systemic concentration of the antitumor agent as compared to underivatized FU.
Chikhale
P J
PJ
Center for Drug Discovery, College of Pharmacy, University of Florida, Gainesville 32610-0497.
Marvanyos
E
E
Bodor
N S
NS
D000042:Absorption; D000279:Administration, Cutaneous; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004058:Diffusion; D005472:Fluorouracil / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D006168:Guinea Pigs; D012867:Skin / Q000378:metabolism; D013329:Structure-Activity Relationship
C091453:1-(carboxypropylcarbamoyl)-5-fluorouracil lipolyl ester; D005472:Fluorouracil