Skin permeation of testosterone and its ester derivatives in rats

To establish the optimum conditions for improving the transdermal delivery of testosterone, we studied the relationship between the lipophilicity of t estosterone ester derivatives and the rat skin permeation rate of testoster one. We performed a rat skin permeation study of testosterone and its comme rcially available ester derivatives, testosterone hemisuccinate, testostero ne propionate and testosterone- 17 beta-cypionate, using an ethanol/water c o-solvent system. The aqueous solubility and rat skin permeation rate of each drug, saturated in various compositions of an ethanol/water system, was determined at 37 d egrees C. The aqueous solubility of testosterone and its ester derivatives increased exponentially as the volume fraction of ethanol increased up to 1 00% (v/v). The stability of testosterone propionate in both the skin homoge nate and the extract was investigated to observe the enzymatic degradation during the skin permeation process. Testosterone propionate was found to be stable in the isotonic buffer solution and in the epidermis-side extract f or 10h at 37 degrees C. However, in the skin homogenate and the dermis-side extract testosterone propionate rapidly degraded producing testosterone, i mplying that testosterone propionate rapidly degraded to testosterone durin g the skin permeation process. The steady-state permeation rates of testost erone in the ethanol/water systems increased exponentially as the volume fr action of ethanol increased, reaching the maximum value (2.69+/-0.69 mu gcm (-2)h(-1)) at 70% (v/v) ethanol in water, and then decreasing with further increases in the ethanol volume fraction. However, in the skin permeation s tudy with testosterone esters saturated in 70% (v/v) ethanol in water syste m, testosterone esters were hardly detected in the receptor solution, proba bly due to the rapid degradation to testosterone during the skin permeation process. Moreover, a parabolic relationship was observed between the perme ation rate of testosterone and the log P values of ester derivatives. Maxim um flux was achieved at a log P value of around 3 which corresponded to tha t of testosterone (log P = 34). The results showed that the skin permeation rate of testosterone and its es ter derivatives was maximized when these compounds were saturated in a 70% ethanolic solution. It was also found that a log P value of around 3 is sui table for the skin permeation of testosterone related compounds.