Abstract 2907: Endoxifen, a potential alternative to 4-OHT gel for chemoprevention
Authors: Lee Oukseub , Ivancic David , Chatterton Robert T. , Khan Seema A. 
Published: February 2011

Background: Topical application of 4-hydroxytamoxifen (4-OHT) to the breast has been reported to inhibit breast tumor cell proliferation to the same degree as the standard dose of oral tamoxifen (TAM) and results in substantially lower systemic effects. Recently, 4-Hydroxy-N-desmethytamoxifen (endoxifen, ENX), another active anti-estrogenic metabolite of TAM has been reported to give a major therapeutic effect because of its abundance and ability to cause proteosomic degradation of ERα. We hypothesize that transdermal permeation of ENX will be significantly enhanced by chemical permeation enhancers (CPEs), making it superior to that of 4-OHT. For the first time, we are reporting the skin permeation of ENX compared to 4-OHT using split-thickness skin of human breast.

Methods: De-identified human skins were obtained from mastectomy specimens with IRB approval. The split-thickness skin were prepared using a surgical dermatome from fresh skin and placed in the MatTek Corp. permeation device (MPD). Procedures for permeation studies were followed as recommended by MatTek Corp. 4-OHT and ENX were prepared in 60 % ethanol/phosphate buffer +/− oleic acid (OA). The receiver solution was phosphate buffered saline (PBS), pH 7.4. 200 µL of the drug solution (40 µg + 0.1µCi of 3H-4-OHT or 3H-ENX) was loaded in the donor chamber. Receiver solutions were stirred at 37° C. The samples of receiver solutions at 24 hr were collected for 3H counting. The percent permeation of the 3H-4-OHT and 3H-ENX was calculated based on the ratio of the amount of 3H-drugs recovered from the receiver to total dose loaded on donor chamber. All permeation experiments were performed in triplicate with a minimum of 4 skin replicates.

Figure 1. Percent permeation of 4-OHT and ENX using split-thickness human skin at 24 h.

Results: Our permeation study using split-thickness skin samples showed relatively small and consistent intra/inter- batch variance in permeation experiments. (figure 1). We found that although the permeation of 4-OHT alone is two-fold higher than that of ENX alone (p=0.006), in the presence of 1 to 2.5% (v/v) of OA, the permeation of ENX was improved by 5 to 7-fold compared to that of ENX alone (p=0.000) and was 2-fold higher than that of 4-OHT+OA (p=0.000). Although the permeation of ENX with OA cotreatment is 1.4%, this is four-fold higher than that of the 4-OHT topical gel being used in a NIH-sponsored clinical trial.

Conclusion: We have found that transdermal permeation of ENX was significantly enhanced in the presence of oleic acid and was superior to that of the 4-OHT topical gel being tested in a current clinical trial. We have been actively screening other CPEs and nano-particles for improving ENX permeation. In addition, we will shortly initiate studies to validate anti-tumor efficacy of ENX in an appropriate animal model for transdermal delivery.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2907.