ATP binding cassette transporters in two distinct compartments of the skin contribute to transdermal absorption of a typical substrate

The role of two ATP binding cassette transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), in transdermal absorption of a typical common substrate was examined in vivo. Skin and plasma concentrations of rhodamine123 (Rho123) after dermal application were reduced in P-gp knockout (mdr1a/1b−/−) mice and were below the detection limit in P-gp and BCRP triple-knockout (mdr1a/1b/bcrp−/−) mice. Lower epidermal-to-hypodermal permeation of Rho123 in mdr1a/1b/bcrp−/− mouse skin compared to the wild-type mouse skin was confirmed in an Ussing-type chamber experiment. The reduction in skin concentration after dermal application in mdr1a/1b/bcrp−/− mice was greater in the dermis than in the epidermis, suggesting functional expressions of these transporters in two distinct skin compartments. Coadministration of the inhibitor itraconazole reduced the skin and plasma concentrations of Rho123 in the wild-type mice, but not in mdr1a/1b/bcrp−/− mice, and a marked decrease of Rho123 concentration was seen in the dermis, demonstrating that the functional activities of these transporters can be modulated in vivo. On the other hand, the distribution of Rho123 after intravenous infusion was higher in mdr1a/1b/bcrp−/− mice than in the wild-type mice. This supports the occurrence of vectorial transport from the skin into systemic circulation, and is consistent with the immunohistochemical localization of P-gp and BCRP in mouse dermal endothelial cells. BCRP was immunohistochemically identified in human epidermis and dermal endothelial cells. Thus, our findings show that ABC transporters in different compartments of the skin contribute to transdermal absorption of a typical substrate in vivo and can be modulated by a specific inhibitor. These findings have implications for transdermal drug delivery. [Display omitted]