Diffusion through the unstirred water layer (UWL) has previously been considered to be the rate limiting step in the intestinal uptake of highly permeable drugs. In order to evaluate the thickness and importance of the UWL, we used previously published effective intestinal permeability (P-eff) data of two high permeability compounds, D-glucose and antipyrine, obtained in single-pass perfusions of the human jejunum. These two compounds are actively and passively transported, respectively, across the jejunal mucosa. The hydrodynamics within the segment is turbulent (well mixed), and higher perfusion rates are assumed to lead to a more efficient luminal stirring, which results in a decreased thickness of the UWL (delta), and consequently, to an enhanced P-eff of rapidly absorbed solutes. Previous published P-eff estimates obtained at a physiological range of perfusion flow rates between 1.5 and 6.0 mi min(-1) were reanalysed, and the overall median delta was estimated to 83 and 188 mu m for D-glucose and antipyrine, respectively. Our main conclusion is that human intestinal effective permeability in vivo of rapidly absorbed compounds is mainly determined by the membrane permeability and not the aqueous permeability. This statement is based on the following observations; (a) no significant differences in either P-eff or delta between the lowest and the highest flow rates of these solutes were observed, (b) despite equal diffusion coefficients in buffer of these two compounds, D-glucose was about 2-3 times more rapidly absorbed than antipyrine, (c) good agreement with recently reported animal and in vitro data. The P-eff estimates of D-glucose (carrier-mediated absorption) and antipyrine (passively absorbed) were highly correlated (r(2) = 0.79; p = 0.0001), which then suggests that the apical membrane of the intestinal mucosa is the main diffusion barrier for both passively and actively absorbed solutes. Furthermore, the membrane area is variable due to nonspecific regulation of the villi and microvilli, which might have a marked influence on the absorption rate. Our results indicate that the clinical relevance of the UWL as a factor responsible for considerable variability in the oral absorption of highly permeable drugs seems unlikely.
