title: Effect of unsaturated menthol analogues on the in vitro penetration of 5-fluorouracil through rat skin.
abstract: To explore the structure-activity relationship for terpenes as transdermal penetration enhancers, unsaturated menthol analogues were synthesized in our study, including p-menth-1-en-3-ol (Compd 1), p-menth-4-en-3-ol (Compd 2), p-menth-4(8)-en-3-ol (Compd 3) and p-menth-8-en-3-ol (Compd 4). Their enhancing activity on the penetration of 5-fluorouracil through rat skin was evaluated by in vitro experiments. Attenuated total reflection-Fourier transform infrared spectroscopy, molecular modeling and transepidermal water loss (TEWL) were introduced to investigate the enhancer induced alteration in different skin lipid domains. The results indicated that Compd 3 achieved the highest enhancement ability with an enhancement ratio of 3.08. Other analogues were less effective than Compd 3, and no significant difference was found between them and menthol. Treatment of rat skin with these enhancers did not produce any shift in the stretching vibration of the methylene in hydrophobic lipid chains, but significantly improved the polar pathway across the rat skin as suggested by the increased TEWL. Molecular modeling results suggested that polar head groups of the skin lipids provided the main binding site for enhancer action. These findings indicated that the studied compounds enhanced drug transport by interacting with the polar domain of the skin lipid, instead of by affecting the arrangement of the hydrophobic chains.
authors: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, People's Republic of China.
authors: Yang
authors: Y
authors: Chen
authors: Jian
authors: J
authors: Wang
authors: Dongmei
authors: D
authors: Cun
authors: Manli
authors: M
authors: Wang
authors: Juan
authors: J
authors: Jiang
authors: Honglei
authors: H
authors: Xi
authors: Hongxia
authors: H
authors: Cui
authors: Yongnan
authors: Y
authors: Xu
authors: Maosheng
authors: M
authors: Cheng
authors: Liang
authors: L
authors: Fang
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D005472:Fluorouracil / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D008055:Lipids / Q000737:chemistry; D008297:Male; D008610:Menthol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000737:chemistry / Q000378:metabolism*; D012869:Skin Absorption; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship
chemical_list: D000964:Antimetabolites, Antineoplastic; D004337:Drug Carriers; D008055:Lipids; D008610:Menthol; D005472:Fluorouracil