Long-Term Permeation Kinetics of Estradiol: (IV) A Theoretical Approach to the Simultaneous Skin Permeation and Bioconversion of Estradiol Esters

Abstract

A theoretical non-steady-state treatment was developed to analyze the kinetics of metabolism during the course of dermal uptake or skin permeation of estradiol esters across the hairless mouse skin. The first-order rate constants for the metabolism reaction of estradiol acetate → estradiol and estradiol diacetate → estradiol acetate → estradiol were determined. The theoretical drug concentration profile calculated from the present model was found to be agreed reasonably well with the experimental data determined in the early stage of skin uptake/metabolism studies (<24 hr). For the skin permeation of estradiol acetate and diacetate and their concurrent metabolism, the experimental Q vs. t profiles were also observed to agree well with the theoretical results for a period of up to 28 hr. A deviation was observed at later phase of experiments, which can be attributed to the reduction in enzyme activity during the permeation studies, possibly due to the result of skin aging.