Effect of dosing volume on gastrointestinal absorption in rats: analysis of the gastrointestinal disposition of L-glucose and estimation of in vivo intestinal membrane permeability.

The effect of the oral dosing volume (DV) on both gastric emptying and intestinal absorption was examined by analyzing the gastrointestinal disposition of a model solute, L-glucose, in rats. The amount of 14C-labeled L-glucose in the gastric and intestinal contents of sacrificed rats was measured at various times after administration, and the data were analyzed with a linear model, assuming first-order gastric emptying followed by first-order intestinal absorption. The gastric emptying rate constant (kg) rose from 0.025 to 0.072 min-1 by increasing DV from 0.1 to 3 mL/rat, whereas the intestinal absorption rate constant (ka) decreased from 0.031 to 0.015 min-1. This decrease in ka was attributed to an increase in the average intestinal lumen volume (Vav) from 24 to 39 microL/cm, assuming that the relationship ka = CLa,app/Vav holds (where CLa,app is the apparent intestinal membrane permeability clearance or the product of the apparent membrane permeability coefficient and surface area). The CLa,app (= kaVav), a measure of the in vivo intestinal membrane permeability, was 0.74 microL/cm/min for a DV value of 0.1 mL/rat and decreased only marginally by 20% for larger values of DV, suggesting an insignificant effect of DV on CLa,app. These results suggest that the accelerating effect of the increased kg, produced by the increased DV on the gastrointestinal absorption, may be canceled by the decrease in ka. A decrease in ka may lead to a decrease in the fraction absorbed. Finally, this study also provides a means for carrying out physiological modeling of drug absorption following oral administration.