In vitro human skin permeation of endoxifen: Potential for local transdermal therapy for primary prevention and carcinoma in situ of the breast

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 EpiDerm™ (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.