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 effciency 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 (3)H/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.