In vitro human skin permeation of endoxifen: potential for local transdermal therapy for primary prevention and carcinoma in situ of the breast
Oukseub Lee1, David Ivancic1, Robert T Chatterton Jr2, Alfred W Rademaker3, Seema A Khan1
1Department of Surgery, 2Department of Obstetrics/Gynecology, 3Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Purpose: Oral tamoxifen, a triphenylethylene (TPE), is useful for breast cancer prevention, but its adverse effects limit acceptance by women. Tamoxifen efficacy is related to its major metabolites 4-hydroxytamoxifen (4-OHT) and N-desmethyl-4-hydroxytamoxifen (endoxifen [ENX]). Transdermal delivery of these to the breast may avert the toxicity of oral tamoxifen while maintaining efficacy. We evaluated the relative efficiency of skin permeation of 4-OHT and ENX in vitro, and tested oleic acid (OA) as a permeation-enhancer.
Methods: 4-OHT, ENX, and estradiol (E2) (0.2 mg/mL of 0.5 µCi 3H/mg) were dissolved in 60% ethanol-phosphate buffer, ±OA (0.1%–5%). Permeation through EpiDermTM (Matek Corp, Ashland, MA) and split-thickness human skin was calculated based on the amount of the agents recovered from the receiver fluid and skin using liquid scintillation counting over 24 hours.
Results: In the EpiDerm model, the absorption of 4-OHT and ENX was 10%–11%; total penetration (TP) was 26%–29% at 24 hours and was decreased by OA. In normal human skin, the absorption of 4-OHT and ENX was 0.3%; TP was 2%–4% at 24 hours. The addition of 1% OA improved the permeation of ENX significantly more than that of 4-OHT (P < 0.004); further titration of OA at 0.25%–0.5% further improved the permeation of ENX to a level similar to that of estradiol.
Conclusion: The addition of OA to ENX results in a favorable rapid delivery equivalent to that of estradiol, a widely used transdermal hormone. The transdermal delivery of ENX to the breast should be further developed in preclinical and clinical studies.
Keywords: endoxifen, breast cancer prevention, human skin, transdermal, oleic acid
This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.Download Article [PDF] View Full Text [HTML][Machine readable]