title: P-Glycoprotein in skin contributes to transdermal absorption of topical corticosteroids.
abstract: ATP binding cassette transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), are expressed in skin, but their involvement in transdermal absorption of clinically used drugs remains unknown. Here, we examined their role in transdermal absorption of corticosteroids. Skin and plasma concentrations of dexamethasone after dermal application were reduced in P-gp and BCRP triple-knockout (Mdr1a/1b/Bcrp-/-) mice. The skin concentration in Mdr1a/1b/Bcrp-/-mice was reduced in the dermis, but not in the epidermis, indicating that functional expression of these transporters in skin is compartmentalized. Involvement of these transporters in dermal transport of dexamethasone was also supported by the observation of a higher epidermal concentration in Mdr1a/1b/Bcrp-/-than wild-type mice during intravenous infusion. Transdermal absorption after dermal application of prednisolone, but not methylprednisolone or ethinyl estradiol, was also lower in Mdr1a/1b/Bcrp-/-than in wild-type mice. Transport studies in epithelial cell lines transfected with P-gp or BCRP showed that dexamethasone and prednisolone are substrates of P-gp, but are minimally transported by BCRP. Thus, our findings suggest that P-gp is involved in transdermal absorption of at least some corticosteroids in vivo. P-gp might be available as a target for inhibition in order to deliver topically applied drugs and cosmetics in a manner that minimizes systemic exposure.
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan; Drug Development Research Laboratories, Drug Metabolism and Pharmacokinetic Research Division, Maruho Company Ltd., Kyoto, Japan. Electronic address: nhashimoto@stu.kanazawa-u.ac.jp.
authors.forename: Naoto
authors.initials: N
authors.lastname: Hashimoto
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan. Electronic address: nakamiti@p.kanazawa-u.ac.jp.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Nakamichi
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan. Electronic address: pcfsts0@stu.kanazawa-u.ac.jp.
authors.forename: Erina
authors.initials: E
authors.lastname: Yamazaki
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan. Electronic address: t0t0r0@stu.kanazawa-u.ac.jp.
authors.forename: Masashi
authors.initials: M
authors.lastname: Oikawa
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan. Electronic address: masuo@p.kanazawa-u.ac.jp.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Masuo
authors.affiliation: The Netherlands Cancer Institute, Division of Molecular Oncology, Amsterdam, The Netherlands. Electronic address: a.schinkel@nki.nl.
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan. Electronic address: ykato@p.kanazawa-u.ac.jp.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kato
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000502:physiology; D000818:Animals; D003907:Dexamethasone / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D012869:Skin Absorption
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; C501412:Abcg2 protein, mouse; D003907:Dexamethasone
keywords: P-glycoprotein; Skin; Topical corticosteroid; Transdermal drug delivery; Transporter