Long-Term Permeation Kinetics of Estradiol: (III) Kinetic Analyses of the Simultaneous Skin Permeation and Bioconversion of Estradiol Esters

Abstract

The skin permeation system developed earlier in this laboratory was utilized to study the kinetics of the simultaneous skin permeation and bioconversion of 5 estradiol esters. The equilibrium solubility of estradiol esters in the lipophilic silicone fluid and in hydrophilic PEG 400/saline solution was found to be dependent upon the alkyl chain length of the esters. Estradiol-3,17-diacetate had a greater solubility in silicone fluid and a lower solubility in PEG 400/saline solution than estradiol-17-acetate. The (skin/silicone fluid) partition coefficients were observed to decrease as the alkyl chain increased in length. During the course of skin permeation, the estradiol esters were metabolized by esterase to regenerate estradiol. The rate of appearance of estradiol from the estradiol esters was observed to be dependent upon the ester concentration on stratum corneum surface and to follow the order of: diacetate > valerate > heptanoate > cypionate > acetate. From the dermal uptake and metabolism studies of estradiol esters the first-order rate constants for the metabolism of estradiol esters were determined. The rate constant for the metabolism of estradiol-3,17-diacetate to form estradiol acetate was observed to be about 22 times faster than the rate constant for the metabolism of estradiol acetate to generate estradiol. The enzymatic hydrolysis of the ester group at 17th position was found also to follow a first-order kinetic process and the rate constants varied with the variation in alkyl chain length.