We may not measure the correct intestinal wall permeability coefficient of drugs: alternative absorptive clearance concept.

It is shown that the conventional method (based on the thin-wall membrane theory) of studying the rate of disappearance or absorption from the lumen alone may not yield the correct intestinal wall (membrane) permeability coefficient of drugs. Potential reasons for causing this problem such as first-pass metabolism and accumulation of drugs in gut wall or tissue as well as back diffusion of drugs from the gut tissue to the lumen (i.e., a part of exsorption phenomenon) and potential major transport barriers across the protoplasm, basal membrane, and basement membrane are discussed. Contrary to the conventional concept, basal and basement membranes should also be considered major barriers for absorption into the blood for compounds with low intestinal permeability, and the protoplasm or cytoplasma should also be considered a major absorption barrier for compounds with high intestinal permeability. Strictly speaking, the conventional experimental method cannot be considered a bona fide method for studying drug permeability that deals with the movement of drug molecules from one side to the other side of a membrane, cell, medium, or device. The wall permeability coefficient thus obtained may therefore not represent the true wall permeability coefficient. "Intestinal absorptive clearance per unit gross surface area" is advocated as the best alternative term because it should more accurately reflect the true meaning of an experimental result for any compounds studied. In contrast to conventional cylindrical, unstirred tube models for the determination of wall permeability coefficients, the absorptive clearance calculation can be made based on a physiologically more realistic model-independent, "flat" or "distended," stirred (not well-stirred) intestinal model. Two model-independent terms, "effective intestinal permeability coefficient" and "effective absorptive permeability coefficient," are recommended as the second alternatives. These terms are theoretically valid for compounds that are not metabolized in the intestinal tissue; they represent the overall permeability across the intestinal tissue (from lumen to blood) under given experimental conditions. Potential shortcomings of using dimensionless wall permeability in the conventional absorption modeling are also discussed.