R ates of intestinal absorption and surface hydrolysis are determined by the interaction of two barriers: poorly stirred fluid adjacent to the mucosa, and the epithelial cell. These two barriers commonly are modeled as a fixed, flat layer of epithelium covered by a fixed thickness of unstirred fluid. To more accurately simulate these barriers in a villous mucosa, maltase activity (measured in vitro) was distributed over an anatomically correct model of rat jejunal villi. We then determined what interaction of the aqueous and epithelial barriers best predicted in vivo maltose hydrolysis rates measured over a broad range of infusate concentrations. Hydrolysis was accurately predicted by a model in which unstirred fluid extended from 20 microm over the villous tips throughout the intervillous space. In this model, the depth of diffusion into the intervillous space is inversely proportional to the efficiency of epithelial handling of the solute. As a result, both the aqueous barrier and the functional surface area are variables rather than constants. Some implications of our findings (relative to the conventional model) include: higher predicted Vmax, efficient handling of low concentrations of a solute at the villous tips while high concentrations must penetrate thick aqueous barriers, and sensitive regulation of transport rates via ease of access to the intervillous space.