Physicochemical model for dose-dependent drug absorption.

A two-tank perfect-mixing tank model was used to stimulate GI absorption. The effect of drug parameters (pK alpha, solubility, and intrinsic wall permeability) and system parameters (pH profile, volume of intestinal contents, and intestinal flow rate) on drug absorption were studied by numerical data stimulation. When the dose did not exceed the solubility of the drug in the intestinal lumen, the fraction absorbed depended on the transit rate relative to the absorption rate and the pK alpha relative to the pH profile, but was independent of drug dose. Saturation of one or both tanks led to dose-dependent absorption. The model was used to simulate absorption of chlorothiazide. Good agreement between simulated and experimental data led to the conclusion that the physical characteristics of chlorothiazide, rather than a saturable transport mechanism at the intestinal wall, may be responsible for the dose-dependent absorption observed for this drug. The model was also used to simulate hydrochlorothiazide absorption. By applying the same system parameters used for chlorothiazide, the model simulation correctly predicted the dose proportionality of hydrochlorothiazide absorption. The lack of dose dependency in this case may be attributed to the higher solubility and pK alpha of hydrochlorothiazide compared with chlorothiazide.