P-Glycoprotein (Abcb1) is involved in absorptive drug transport in skin

• Published in: Journal of controlled release 2008-11, Vol.131 (3), p.198-204
• Main Authors: Ito, Katsuaki, Nguyen, Hai Thien, Kato, Yukio, Wakayama, Tomohiko, Kubo, Yoshiyuki, Iseki, Shoichi, Tsuji, Akira
• Format: Article
• Language: English
• Subjects: ABCB1; Animals; Antifungal Agents - metabolism; ATP Binding Cassette Transporter, Sub-Family B - antagonists & inhibitors; ATP Binding Cassette Transporter, Sub-Family B - genetics; ATP Binding Cassette Transporter, Sub-Family B - metabolism; Biological and medical sciences; Biological Transport - genetics; Fluorescent Dyes - metabolism; Gene Knockout Techniques; General pharmacology; Immunohistochemistry; Itraconazole - metabolism; Male; Medical sciences; Mice; Mice, Knockout; P-glycoprotein; Permeability; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Propranolol - administration & dosage; Rhodamine 123 - metabolism; Skin; Skin - metabolism; Skin Absorption - genetics; Substrate Specificity; Tissue Distribution - genetics; Transdermal permeation; Transporter
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2008.08.004

The purpose of the present study was to investigate the role of P-glycoprotein (P-gp) in drug disposition in skin. The distribution of P-gp substrates (rhodamine 123 and itraconazole) to the skin after administration from the epidermal side was lower in P-gp gene knockout ( mdr1a/1b −/− ) mice than that in wild-type mice. Coadministration of propranolol, a P-gp inhibitor, decreased the distribution of itraconazole to the skin in wild-type mice, but not in mdr1a/1b −/− mice. These results suggest that P-gp contributes to the influx (from the epidermal side) of its substrates into skin, although P-gp is generally involved in efflux of drugs from various tissues. This finding was supported by the lower vectorial transport of rhodamine 123 from the epidermal to the hypodermal side in mdr1a/1b −/− mice in Ussing-type chamber experiments and by the immunohistochemical localization of P-gp throughout the dermal layer. Distribution of itraconazole after intravenous administration, on the other hand, was higher in mdr1a/1b −/− mice than that in wild-type mice, suggesting that P-gp transports this drug from the skin to the circulation. The present findings are the first to demonstrate involvement of P-gp in dermal drug disposition.