Verification of P-Glycoprotein Function at the Dermal Barrier in Diffusion Cells and Dynamic “Skin-On-A-Chip” Microfluidic Device

Abstract

The efficacy of transdermal absorption of drugs and the irritation or corrosion potential of topically applied formulations are important areas of investigation in pharmaceutical, military and cosmetic research. The aim of the present experiments is to test the role of P-glycoprotein in dermal drug delivery in various ex vivo and in vitro platforms, including a novel microchip technology developed by Pázmány Péter Catholic University. A further question is whether the freezing of excised skin and age have any influence on P-glycoprotein-mediated dermal drug absorption. Two P-glycoprotein substrate model drugs (quinidine and erythromycin) were investigated via topical administration in diffusion cells, a skin-on-a-chip device and transdermal microdialysis in rat skin. The transdermal absorption of both model drugs was reduced by P-glycoprotein inhibition, and both aging and freezing increased the permeability of the tissues. Based on our findings, it is concluded that the process of freezing leads to reduced function of efflux transporters, and increases the porosity of skin. P-glycoprotein has an absorptive orientation in the skin, and topical inhibitors can modify its action. The defensive role of the skin seems to be diminished in aged individuals, partly due to reduced thickness of the dermis. The novel microfluidic microchip seems to be an appropriate tool to investigate dermal drug delivery.

Development of Skin-On-A-Chip Platforms for Different Utilizations: Factors to Be Considered

“…As an animal skin model, the pig skin is described as the best comparable model of the human skin, both structurally and the barrier function [ 23 , 24 ] ( Table 2 ). The excellent availability is also an essential point of the use of excised porcine skins.…”

“…The excellent availability is also an essential point of the use of excised porcine skins. Rat skin is also widely used for dermal penetration studies [ 24 , 25 , 26 ]. Rat skin is employed in the plant protection field for toxicology studies and in-vivo skin absorption studies (transdermal microdialysis).…”

“…Our research group constructed a similar platform [ 24 , 26 ]. In this microfluidic chip, human and animal excised skin samples were used in permeability testing.…”

“…Our laboratory validated the system also functionally for testing transdermal absorption of topically applied P-glycoprotein substrates (quinidine and erythromycin). The effect of freezing and thawing on the efflux transporter function at the epidermis and dermis border zone was also successfully evaluated in the microchip [ 24 ].…”

“…Two P-glycoprotein model substrates (erythromycin and quinidine) were tested in cream and gel formulation in an ex vivo skin-on-a-chip instrument. The device’s parallelization can also be implemented, as demonstrated in the study [ 24 ]. The findings indicate that the skin-chip system is an appropriate solution for the screening of skin penetration and drug-drug interactions in the dermal barrier.…”