Unstirred layer, source of biased Michaelis constant in membrane transport.

In anaesthetized rats the rate of appearance of benzoic acid and aminopyrine in jejunal venous blood was measured; the pH of the luminal perfusion solution was varied between 4 and 10.5. The pH-absorption curves were less steep than predicted by the unmodified pH-partition theory. A reduction of the mucosal unstirred layer thickness by means of the segmented-flow technique considerably increased the absorption rate without essentially changing the shape of the pH-absorption curves. The pH at the surface of the jejunal mucosa was 6.0, 6.5, 6.6, and 8.0 for luminal solutions of pH 4.0, 6.0, 8.0, and 10.8, respectively. From the absorption data the microclimate-pH was calculated which would explain best the observed pH-absorption curves. These calculated pH-values correspond well to the values measured at the mucosal surface. Therefore, it was concluded that a microclimate-pH caused the deviation of the intestinal pH-absorption curves of benzoic acid and aminopyrine from the prediction of the unmodified pH-partition theory. The mucosal unstirred layer represented only a considerable permeation resistance and was not responsible for the deviating shape of the pH-absorption curves.

Drug absorption by the rat jejunum perfused in situ. Dissociation from the pH-partition theory and role of microclimate-pH and unstirred layer.

The appearance rate of butanol, antipyrine, salicylic acid, and urea in the venous blood of rat jejunal loops perfused in vivo is increased up to 64%, if the intraluminal solution is mixed more efficiently by the simultaneous perfusion of air. The enhancement of the absorption can be attributed partly to the enlarged absorbing area but mainly to the reduction of the effective unstirred layer thickness by about 500 μm. The unstirred layer reduces the phenylalanine absorption at 0.1 mmol l−1 but not at 100 mmol l−1, since at high concentrations a full saturation of the transport system can be achieved in spite of the unstirred layer resistance. The interference of the unstirred layer increases with increasing absorbability of the substances.

Dependence of intestinal absorption in vivo on the unstirred layer.

The conditions for deviations of thepH-absorption curve from the course predicted by the simplepH partition theory are investigated theoretically. The deviations are an elevation of the asymptotic section usually approaching zero and/or a shift of the intermediate section, more exactly of the inflection point, in the direction of the abscissa and/ or the ordinate. In the absence of a specialpH at the surface of the barrier (microclimatepH), the elevation of the asymptotic section can be attributed to a permeability of the barrier to the ionized form of the permeating substance. A shift of the inflection point to the right for acids and to the left for bases can be explained by a significant unstirred layer at the surface of the barrier or-only when the concentration in the well- stirred bulk phase is decreasing with time-by a high distribution ratio of the substance between barrier and bulk phase. A variable microclimatepH influenced by bulk phasepH can also produce the described deviations.

Shift of pH-absorption curves.

The effective unstirred layer thickness in the rat jejunum perfused in vivo amounts to at least 530 μm. This value has been estimated from the absorption increase ofl-phenylalanine due to better mixing of the luminal solution by air bubbles.

Unstirred layer thickness in perfused rat jejunum in vivo.

1

Jejunal loops in anaesthetized rats were perfused with14C-labelled urea, methanol, and ethanol in buffered isotonic saline solutions at pH 7 The blood flow, the disappearance rate from the intestinal lumen and the appearance rate in the intestinal venous blood were determined simultaneously




2

A decrease of the blood flow from about 18 to 02 ml min−1 g−1 wet tissue diminished the disappearance and appearance rate of the substances and eventually their metabolites An increase of the blood flow caused the reverse results The dependence on blood flow was greater for the appearance than for the disappearance rate The two transfer rates and their dependence on blood flow were smaller for urea than for methanol and ethanol




3

The experimental data are discussed by means of one three- and two four-compartment models Blood flow independent permeability coefficients for the intestinal epithelium were derived: urea 0062±0015, methanol 023±006, ethanol 024±009 ml min−1 g−1 The permeability coefficients for the subepithelial tissue were also calculated: urea 005±002, methanol 0066±0007, ethanol 0081±0015 ml min−1 g−1

J. Remischovsky

Papers

Der Einfluß der Durchblutung auf die Resorption von Harnstoff, Methanol und Äthanol aus dem Jejunum der Ratte