EXPERIMENTAL ESTIMATION OF THE EFFECTIVE UNSTIRRED WATER LAYER THICKNESS IN THE HUMAN JEJUNUM, AND ITS IMPORTANCE IN ORAL-DRUG ABSORPTION

Diffusion through the unstirred water layer (UWL) has previously been considered to be the rate limiting step in the intestinal uptake of hi ghly permeable drugs. In order to evaluate the thickness and importanc e of the UWL, we used previously published effective intestinal permea bility (P-eff) data of two high permeability compounds, D-glucose and antipyrine, obtained in single-pass perfusions of the human jejunum. T hese two compounds are actively and passively transported, respectivel y, 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 th ickness 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 m i min(-1) were reanalysed, and the overall median delta was estimated to 83 and 188 mu m for D-glucose and antipyrine, respectively. Our mai n conclusion is that human intestinal effective permeability in vivo o f rapidly absorbed compounds is mainly determined by the membrane perm eability 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 s olutes were observed, (b) despite equal diffusion coefficients in buff er of these two compounds, D-glucose was about 2-3 times more rapidly absorbed than antipyrine, (c) good agreement with recently reported an imal and in vitro data. The P-eff estimates of D-glucose (carrier-medi ated absorption) and antipyrine (passively absorbed) were highly corre lated (r(2) = 0.79; p = 0.0001), which then suggests that the apical m embrane of the intestinal mucosa is the main diffusion barrier for bot h passively and actively absorbed solutes. Furthermore, the membrane a rea is variable due to nonspecific regulation of the villi and microvi lli, which might have a marked influence on the absorption rate. Our r esults indicate that the clinical relevance of the UWL as a factor res ponsible for considerable variability in the oral absorption of highly permeable drugs seems unlikely.