P-glycoprotein (Abcb1) is involved in absorptive drug transport in skin.
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.
Ito
Katsuaki
K
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Nguyen
Hai Thien
HT
Kato
Yukio
Y
Wakayama
Tomohiko
T
Kubo
Yoshiyuki
Y
Iseki
Shoichi
S
Tsuji
Akira
A
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D000935:Antifungal Agents / Q000378:metabolism; D001692:Biological Transport / Q000235:genetics; D005456:Fluorescent Dyes / Q000378:metabolism; D055786:Gene Knockout Techniques; D007150:Immunohistochemistry; D017964:Itraconazole / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability; D011433:Propranolol / Q000008:administration & dosage; D020112:Rhodamine 123 / Q000378:metabolism; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption / Q000235:genetics; D013379:Substrate Specificity; D014018:Tissue Distribution / Q000235:genetics
D018435:ATP Binding Cassette Transporter, Subfamily B; D000935:Antifungal Agents; D005456:Fluorescent Dyes; D020112:Rhodamine 123; D017964:Itraconazole; D011433:Propranolol