title: Percutaneous absorption and metabolism of [14C]-ethoxycoumarin in a pig ear skin model.
abstract: The biotransformation of chemicals by the skin can be a critical determinant of systemic exposure in humans following dermal absorption. Pig ear skin, which closely resembles human skin, is a candidate ex vivo alternative model for the investigation of xenobiotics penetration and metabolism. We developed an ex vivo pig ear skin model and explored its absorption, diffusion and metabolic capabilities using the model compound (14)C-ethoxycoumarin (7-EC). Experimentations were undertaken on pig ear skin explants after application of various (14)C-EC doses. Diffusion was quantified as well as the production of 7-EC metabolites resulting from phases I and II enzyme activities, using radio-HPLC. After 48h, most of the radioactivity was absorbed and was recovered in culture media (70%) or in the skin itself (10%). 7-EC metabolites were identified as 7-hydroxycoumarin (OH-C) and the corresponding sulfate (S-O-C) and glucuronide (G-O-C) conjugates. Their formation followed Michaelis-Menten kinetics with saturation reached around 100 microM of 7-EC. Results demonstrate that dermal absorption as well as phases I and II enzymatic activities of pig skin are both functional. This model should represent a valuable alternative for the study of the transdermal exposure to chemicals, combining a functional dermal barrier and active biotransformation capabilities.
authors.affiliation: INRA, UMR 1089 Xénobiotiques, 180 Chemin de Tournefeuille, BP 93173, 31027 Toulouse Cedex 3, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Jacques
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Perdu
authors.forename: Céline
authors.initials: C
authors.lastname: Dorio
authors.forename: Daniel
authors.initials: D
authors.lastname: Bacqueville
authors.forename: Alain
authors.initials: A
authors.lastname: Mavon
authors.forename: Daniel
authors.initials: D
authors.lastname: Zalko
mesh_terms: D000042:Absorption; D000818:Animals; D001711:Biotransformation; D003374:Coumarins / Q000493:pharmacokinetics*; D004431:Ear, External; D066298:In Vitro Techniques; D023421:Models, Animal; D012867:Skin / Q000201:enzymology / Q000378:metabolism*; D013552:Swine; D015262:Xenobiotics / Q000493:pharmacokinetics*
chemical_list: D003374:Coumarins; D015262:Xenobiotics; C017299:7-ethoxycoumarin