title: Percutaneous penetration of fluorescein isothiocyanate-dextrans and the mechanism for enhancement effect of enhancers on the intercellular penetration.
abstract: To identify the mechanism involved in the enhancement effect of enhancers on the intercellular penetration of large polar molecules, the skin penetration of fluorescein isothiocyanate (FITC)-dextrans (average molecular weight; 4400, 9400, and 69000 Da) and the lipid removal from the intercellular spaces by enhancers were studied using hairless rat skin. Pretreatment of hairless rat skin with enhancers such as n-octanol (20%), laurocapram (2%), isopropylmyristate (IPM, 20%), oleic acid (5%) and cineol (2%), which are water-immiscible, significantly enhanced the flux of FITC-dextrans, while pretreatment with water-miscible enhancers, i.e. dimethyl sulfoxide (DMSO, 5%) and N-methyl-2-pyrrolidone (NMP) did not increase the flux compared with the control. The penetration of FITC-dextrans was approximately size dependent. n-Octanol, laurocapram, IPM and oleic acid dramatically removed ceramides which are the intercellular lipids, whereas NMP and DMSO partly extracted the sphingolipids. A linear relationship was observed between the flux and removal of ceramides (p < 0.01), indicating that the removal of intercellular lipids would cause dramatic dilations between adherent cornified cells and enhance the penetration through the intercellular pathways. When the penetration of FITC-dextrans through Wistar rat skin was compared with that via hairless rat skin, the steady state flux of FITC-dextrans through Wistar rat skin pretreated with water-immiscible enhancers was 1.2- to 4.9-fold higher, suggesting that the penetration of large polar molecules through follicles may play at least some role in the percutaneous absorption.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kinki University, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ogiso
authors.forename: T
authors.initials: T
authors.lastname: Paku
authors.forename: M
authors.initials: M
authors.lastname: Iwaki
authors.forename: T
authors.initials: T
authors.lastname: Tanino
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D002518:Ceramides / Q000737:chemistry; D003511:Cyclohexanols; D003911:Dextrans / Q000493:pharmacokinetics*; D004817:Epidermis / Q000737:chemistry / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology; D000077591:Eucalyptol; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D008055:Lipids / Q000737:chemistry; D008297:Male; D008610:Menthol / Q000031:analogs & derivatives / Q000494:pharmacology; D039821:Monoterpenes; D009226:Myristates / Q000494:pharmacology; D019301:Oleic Acid; D009829:Oleic Acids / Q000494:pharmacology; D010592:Pharmaceutic Aids / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000737:chemistry; D012869:Skin Absorption / Q000187:drug effects*; D013107:Sphingolipids / Q000737:chemistry; D013729:Terpenes
chemical_list: D001381:Azepines; D002518:Ceramides; D003511:Cyclohexanols; D003911:Dextrans; D008055:Lipids; D039821:Monoterpenes; D009226:Myristates; D009829:Oleic Acids; D010592:Pharmaceutic Aids; D013107:Sphingolipids; D013729:Terpenes; C015219:fluorescein isothiocyanate dextran; C008205:isopropyl myristate; D008610:Menthol; C035229:laurocapram; D019301:Oleic Acid; D000431:Ethanol; D016650:Fluorescein-5-isothiocyanate; D000077591:Eucalyptol