Effect of ‘unstirred’ water layer in the intestine on the rate and extent of absorption after oral administration

Abstract

The presence of an aqueous diffusion layer or 'unstirred' water layer adjacent to the intestinal membrane has long been regarded as a potential barrier for intestinal absorption of compounds. Theoretical analyses were performed in the present study to quantitatively determine the effect of this layer on the rate and extent of absorption of passively absorbed compounds with different membrane absorption half-lives (10 to 300 min) in humans, dogs, rabbits, rats and mice. Diffusion half-lives across this (40 microns thick) layer were estimated to be 5.8, 2.5, 1.1, 0.65 and 0.32 min, respectively, in the distended intestine of the above five species. These half-lives are reduced by about 5-fold when the intestine is about 80% 'flat' in fasting state. The results of extensive analysis indicate that the presence of such a layer is generally expected to have a relatively mild or insignificant effect on the rate of absorption and an insignificant effect on the extent of absorption. The study also indicates that an aqueous layer of 708 microns has practically no effect on the extent of absorption of progesterone, a highly lipophilic compound, in rats. For prediction of or correlation with the fraction of oral dose absorbed after oral administration, the present study indicates that use of apparent or effective permeability rather than unbiased or true wall (membrane) permeability, as advocated earlier by others, should generally suffice.

P-Glycoprotein and an Unstirred Water Layer Barring Digoxin Absorption in the Vascularly Perfused Rat Small Intestine Preparation: Induction Studies with Pregnenolone-16α-carbonitrile

“…The presence of the UWL, together with the Pgp, compounded the problem in lowering F. The UWL, with a thickness estimated at 100 to 800 m or less, has long been recognized as a potential barrier for intestinal absorption of compounds (Lewis and Fordtran, 1975;Ho et al, 1983;Chiou, 1994). Permeation of drugs within the UWL was modeled as a simple diffusion process in a water layer.…”

“…d Calculated according to the radius of small intestine, 0.18 cm (Chiou, 1994), thickness of unstirred water layer, 100 m (Anderson et al, 1988), and lipid bilayer membrane, 10 nm, and small intestine of length 100 cm.…”

Oral Absorption, Intestinal Metabolism and Human Oral Bioavailability

“…The thickness of this layer in humans is only 25 μm (Strocchi et al 1996). Chiou et al quantitatively studied the impact of the unstirred water layer adjacent to the intestinal membrane on the rate and extent of absorption of passively absorbed drugs with different membrane absorption half-lives (10 -300 min) in humans (Chiou 1994). Results of this analysis suggested that the presence of the unstirred water layer is generally expected to have a relatively mild or insignificant effect on the rate of absorption and an insignificant effect on the extent of absorption (Kimura and Higaki 2002).…”

Anatomical and Physiological Factors Affecting Oral Drug Bioavailability in Rats, Dogs, and Humans

“…Adjacent to the intestinal membrane is an unstirred water layer that is a potential barrier for the absorption of various drug molecules across the intestinal membrane. The thickness of this layer in rats is about 100 μm, while in humans and dogs it is 40 μm (Chiou, 1994). Chiou et al evaluated the impact of the unstirred water layer adjacent to the intestinal membrane on the rate and extent of absorption for passively absorbed drugs with different membrane absorption half-lives (10-300 min) in humans, dogs, rabbits, rats, and mice.…”