Cutaneous estradiol permeation, penetration and metabolism in pig and man.
OBJECTIVE
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. 17beta-Estradiol (E(2)), which is highly metabolized by skin cells, serves as model drug since E(2) application is of high relevance in hormone replacement therapy while topical E(2) may promote wound healing. E(2) TTS, gel and an ethanolic solution were investigated for cutaneous penetration, permeation and metabolism.


RESULTS
E(2) TTS enabled an E(2) uptake of 42.9% of the applied dose accompanied by a high percentage of E(2) 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 E(2) uptake of 41.7 and 22.9% of the applied dose accompanied by a high E(2) 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 E(2) permeation and metabolism were clearly diminished. Most importantly, the in vitro models proved to be predictive with respect to the E(2)/estrone ratio in female plasma under transdermal hormone replacement therapy.


CONCLUSIONS
In vitro tests should reduce the need for both animal and human studies for cutaneous uptake and metabolism in the future.
Mahmoud
A
A
Institut für Pharmazie, Pharmakologie und Toxikologie, Freie Universität Berlin, Königin-Luise-Strasse 2-4, DE-14195 Berlin, Germany.
Haberland
A
A
Dürrfeld
M
M
Heydeck
D
D
Wagner
S
S
Schafer-Korting
M
M
D000279:Administration, Cutaneous; D000818:Animals; D016503:Drug Delivery Systems; D004817:Epidermis / Q000378:metabolism; D004958:Estradiol / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004970:Estrone / Q000378:metabolism; D005260:Female; D005552:Forelimb; D005782:Gels; D006801:Humans; D066298:In Vitro Techniques; D008954:Models, Biological; D010477:Perfusion; D010539:Permeability; D011863:Radioimmunoassay; D012869:Skin Absorption; D012997:Solvents; D013552:Swine; D013997:Time Factors
D005782:Gels; D012997:Solvents; D004970:Estrone; D004958:Estradiol