Topical vaginal drug delivery I: effect of the estrous cycle on vaginal membrane permeability and diffusivity of vidarabine in mice.

Preliminary studies showed that the vaginal membrane permeability coefficients for vidarabine (9-beta-D-arabinofuranosyladenine) varied widely within a group of mice of the same species and age. This finding prompted an investigation of the influence of the female mouse sexual cycle on the vidarabine permeability. By means of a vaginal smear technique, the sexual cycle, which was approximately 5 days in duration, was divided into five phases. The vaginal membrane permeability of vidarabine was determined during each phase. The results revealed that the permeability coefficients for vidarabine during the diestrus phase (3 X 10(-6)-4 X 10(-5) cm/sec) were 10-100 times higher than those obtained at the early estrus or estrus phases (1-3 X 10(-7) cm/sec). Further permeation studies on membranes at early estrus and estrus were performed by separating the cornified layer from the noncornified portion of the membrane. The low permeability coefficient of vidarabine across the cornified layer (4 X 10(-7) cm/sec) suggests that this layer may be the major diffusion barrier for vidarabine when the drug is topically applied. Collectively, the data also suggest that during estrus a three-layer diffusion model is appropriate, that during early diestrus a single-layer diffusion model may apply, and that during proestrus and postestrus the situations are intermediate and more complicated.