Cutaneous Estradiol Permeation, Penetration and Metabolism in Pig and Man

Abstract

Aim and Methods: Drug development in dermatotherapy and also development of transdermal therapeutic systems (TTS) demand high-predictive in vitro models to estimate drug levels in skin and systemic uptake. Here we compare three ready-to-use models, reconstructed human epidermis, split porcine skin and the perfused porcine forelimb. 17β-Estradiol (E₂), which is highly metabolized by skin cells, serves as model drug since E₂ application is of high relevance in hormone replacement therapy while topical E₂ may promote wound healing. E₂ TTS, gel and an ethanolic solution were investigated for cutaneous penetration, permeation and metabolism. Results: E₂ TTS enabled an E₂ uptake of 42.9% of the applied dose accompanied by a high percentage of E₂ metabolism (30% of the penetrated dose) in the perfused porcine forelimb. In Franz cell experiments with reconstructed human epidermis and split porcine skin, the gel allowed an E₂ uptake of 41.7 and 22.9% of the applied dose accompanied by a high E₂ metabolism (42.6 and 28.6% of the penetrated dose). Due to toxic effects of the vehicle, this was not true with an ethanolic solution, then E₂ permeation and metabolism were clearly diminished. Most importantly, the in vitro models proved to be predictive with respect to the E₂/estrone ratio in female plasma under transdermal hormone replacement therapy. Conclusion: In vitro tests should reduce the need for both animal and human studies for cutaneous uptake and metabolism in the future.

Qualitative detection of single submicron and nanoparticles in human skin by scanning transmission x-ray microscopy

“…In fact, various studies demonstrated that in vitro investigations on porcine ear skin is well suited as a model for in vivo human skin applying different methods of investigation. These concern, e.g., tape stripping in combination with transepidermal water loss and impedance spectroscopy, 58 light microscopy, transmission electron microscopy, and cryo scanning electron microscopy, 59 studies with diffusion cells, 59,60 reconstructed skin, 61 penetration studies applying laser scanning microscopy and biopsies 62 as well as the comparison of stratum corneum thickness, diameters of hair and infundibula. 63 …”

Cutaneous Metabolism in Transdermal Drug Delivery

“…The isolated perfused porcine skin flap and the single-pass perfused rabbit ear have been introduced and well developed as a humane alternative animal model, with benefits in maintaining the physical permeation barrier of the stratum corneum and the viable metabolic layers of the epidermis, as well as achieving perfusion of the underlying vasculated tissue similar to the natural blood flow [14,[23][24][25]. Recently, the perfused porcine forelimb was introduced as a ready-to-use in vitro model to estimate cutaneous permeation and metabolism of 17 -estradiol [26].…”

Which Skin Model Is the Most Appropriate for the Investigation of Topically Applied Substances into the Hair Follicles?

“…Porcine tissue is a highly suitable model for human skin, offering a very similar tissue structure [28][29][30][31] . In particular, porcine ear skin has the advantage of possessing an intact skin barrier on the upper side, while being still fixed to the cartilage [28,32] .…”