Drug delivery of topical microbicidal molecules against HIV offers promise as a modality to prevent sexual transmission of the virus. Success of any microbicide product depends, in an interactive way, upon its drug (the microbicide active pharmaceutical ingredient, API) and its delivery system (e.g. a gel, film or intravaginal ring). There is a widespread agreement that more effective drug delivery vehicles, as well as better APIs, must be developed to improve the efficacy of microbicide products. Non-Newtonian gels are primary microbicide vehicles, but those to date have been created with limited understanding of how their properties govern their spreading and retention in the vagina, which, in turn, govern successful drug delivery. Here, we apply fundamental fluid mechanical and physicochemical transport theory to help better understand how successful microbicide API delivery depends upon properties of a gel and the vaginal environment. We address several critical components of this complex process, including: elastohydrodynamic flow of the bolus of a non-Newtonian fluid; and mass transfer due to inhomogeneous dilution of the gel by vaginal fluid contacting it along a moving boundary (the locally deforming vaginal epithelial surface). Local dilution of gel alters local rheological properties. We evaluated this experimentally, delin-eating the way that constitutive parameters of a shear-thinning gel are modified by dilution. We supplement the Reynolds lubrication equation with a mass conservation equation to model diluting fluid movement across the moving vaginal epithelial surface and into the gel bolus. This is a physicochemically complex phenomenon that is not well understood. We implement a boundary flux model based upon the elevated hydrodynamic pressures in the cells. Results show that this model produces fluxes that lie within the range of mean values that have been reported. Further experimental characterization of the vaginal wall is required for a more precise set of parameters and a more sophisticated theoretical treatment of epithelium. (C) 2012 Elsevier B.V. All rights reserved.