Enhancement by terpenes of 5-fluorouracil permeation through the stratum corneum: model solvent approach.
5-Fluorouracil permeates the stratum corneum through the intercellular pathway. 5-Fluorouracil is hydrophilic and, therefore, its partitioning from the aqueous region into the hydrocarbon interior of stratum corneum lipids is expected to be an important stage of its permeation and a target for some permeation enhancers. It has also been reported that complexation plays a role in the enhancement effect of some accelerants. These mechanisms have been investigated. For partitioning-permeation studies, isooctane was chosen as a model of the hydrocarbon interior of stratum corneum lipid bilayers and the effects of 26 different terpene enhancers on the solubility of 5-fluorouracil in isooctane were measured. Results were then compared with the effects of the same enhancers on the permeation of 5-fluorouracil through the epidermis in man. The stoichiometry of interaction of cineole and limonene with 5-fluorouracil were also studied to reveal possible complex formation. Solubility studies revealed good correlation between solubility and enhancement ratios for the majority of terpenes, indicating that one mechanism by which terpenes increase permeation of the stratum corneum by 5-fluorouracil is by improvement of partitioning. Stoichiometry studies showed that cineole can form 1:1 or higher complexes with 5-fluorouracil. With limonene, only a weak 1:1 complex was indicated. Data obtained using epidermis from man show that the enhancement effect of cineole toward 5-fluorouracil is much higher than that of limonene. These data reveal that terpenes might increase the permeation of 5-fluorouracil through the stratum corneum as a result of complex formation and a form of facilitated transport.
Moghimi
H R
HR
School of Pharmacy, Shaheed Beheshti University of Medical Sciences, Tehran, Iran.
Williams
A C
AC
Barry
B W
BW
D000963:Antimetabolites / Q000493:pharmacokinetics*; D004357:Drug Synergism; D005472:Fluorouracil / Q000493:pharmacokinetics*; D006801:Humans; D008956:Models, Chemical; D010539:Permeability / Q000187:drug effects*; D012867:Skin / Q000378:metabolism*; D012995:Solubility; D012997:Solvents / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013729:Terpenes / Q000494:pharmacology*
D000963:Antimetabolites; D012997:Solvents; D013729:Terpenes; D005472:Fluorouracil