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.
Highlights
Our largest organ, the skin, is a place for the application of cosmetics and drugs for different therapeutic purposes
The aims of the current study were: (1) to determine the skin penetration of two P-gp substrate model drugs in the presence or absence of a transporter modulator; (2) to determine whether the freezing of the skin samples had an influence on the drug absorption and P-gp function; (3) to compare the model drug penetration in aged and young rat abdominal skins; (4) to make an ex vivo/in vivo correlation assessment between drug penetration in diffusion cells or in transdermal microdialysis in anesthetized rats; and (5) to test our skin-on-a chip microfluidic system for applicability for transdermal drug delivery and transporter interaction at the dermal barrier
Erythromycin was used as a suspension formulation dispersed in a basic cream or as a commercially available cream (Aknemycin®), and quinidine was applied as a suspension cream or was fully dissolved in a basic gel
Summary
The skin, is a place for the application of cosmetics and drugs for different therapeutic purposes (both local and systemic). Transdermal drug delivery offers an advantageous route of drug administration by eliminating first-pass hepatic metabolism, resulting in fewer systemic side effects [1] and providing sustained drug release for a prolonged period of time. It is a noninvasive route of drug administration, and offers superior patient compatibility compared to the use of numerous injections. In addition to its role as a barrier, both physical and biological, skin is a transport regulator It regulates the influx and efflux of water molecules into and out of the body. It makes possible the uptake of a variety of small molecules that are quite lipophilic (partition coefficient, logP > 1.5) and have a low molecular weight, i.e., less than 500 Da [2]
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