Abstract 5566: In vitro human skin permeation enhancement of endoxifen by oleic acid
Authors: Lee Oukseub , Ivancic David , Chatterton Robert T. , Khan Seema A. 
Published: June 2012

Background: Oral medication for breast cancer prevention is associated with systemic exposure and resulting adverse effects; there is a need for alternative drug delivery approaches. Transdermal drug delivery is such an option, and 4-Hydroxy-N-desmethytamoxifen (endoxifen, ENX) is an excellent candidate for development for this route. ENX is an active metabolite of tamoxifen with major therapeutic effect related to potent estrogen antagonism and ability to cause proteosomic degradation of ERα. We hypothesize that skin permeation of ENX with oleic acid (OA) will be equivalent or superior to that of estradiol (E2), which is a well-established transdermal agent.

Methods: Split-thickness human skin samples (354 ± 25 micron) were prepared from de-identified fresh mastectomy specimens under an IRB approved protocol using a surgical blade and placed in Franz diffusion cells (PermeGear, Inc.). ENX was prepared in 60 % (v/v) ethanol/phosphate buffer (PB) +/- OA (0.1to 1% v/v). E2 was used as a positive control drug, prepared in 60 % ethanol/PB. The receiver fluid was PBS, pH 7.4 with 4% (w/v) polyoxyethylene 20 oleyl ether (Sigma-Aldrich). 100 µL of the drug solution (30 µg + 0.1µCi of 3H-E2 or 3H-ENX) was loaded in the donor chamber. Receiver fluid was stirred at 37° C. A sample of receiver fluid was collected for 3H counting from 4 to 24 hr point with 2 hr interval. Each permeation experiment was performed in duplicate for each treatment condition using the breast skin of one individual. The permeation experiments were repeated three times with the skin from different individuals.

Results: Results were expressed as the mean and standard deviation (SD) of the % of the applied dose. Absorption is defined as the amount of drug passing into the receiver fluid. We found that the absorption of E2 was 0.2 ± 0.17% (at 12hr) and 3.16 ± 2.79 % (at 24hr) of the applied dose while the absorption of ENX was 0.07± 0.08 % (at 12hr) and 1.45 ± 1.07 % (at 24hr). In the presence of OA, the permeation of ENX was enhanced by 2 to 12- fold at 12 hr and by 1.2 to 3.8- fold at 24 hr. At the 12 hr point, the absorption of ENX alone is one third of that of E2 alone (p = 0.09) however in the presence of 0.25, 0.5, and 1% (v/v) of OA, the absorption of ENX was by 4.4-fold (p = 0.02), 6.4-fold (p = 0.01), and 3-fold (p = 0.02) higher than E2, respectively. At 24 hr, there was no further significant enhancement in the absorption of ENX by 0.25 and 0.5% of OA compared to that of E2. The addition of 0.1 and 1% OA made the absorption of ENX retarded than that of E2 at 24 hr.

Conclusion: The skin permeation of ENX was significantly enhanced in the presence of 0.25-1 % of oleic acid and was superior to that of E2 alone at 12 hr. Our results imply that the topical delivery of endoxifen is a potential option for breast cancer prevention with no or minimal systemic toxicity/side effects. Efficacy remains to be demonstrated, but is highly likely given the data on the parent compound (tamoxifen).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5566. doi:10.1158/1538-7445.AM2011-5566