New perspectives on the theory of permeability and resistance in the study of drug transport and absorption.

Permeability coefficient (P) expressed as distance per unit time has been commonly interpreted to represent the velocity of drug movement across a heterogeneous medium such as skin and intestinal epithelium. The basis of such an interpretation is questioned on several grounds. For example, the basic assumption for calculating P (as defined conventionally) according to the Fick's law of diffusion requires the entire medium to be homogeneous and rate-limiting in transport. The theoretical basis of the widely used total resistance or resistance additivity concept is reviewed. Such a concept is shown to be applicable to the study of total transit time across the medium but may not be applicable to the study of steady-state flux or absorption across the medium under normal conditions. Based on the diffusional, compartmental, absorptive clearance or carrier-mediated-transport analysis it is shown that only the first transport resistance from the bulk medium across the surface (such as cellular membranes) of the permeation medium (such as a cell or a tissue) is usually the deciding factor in drug transport or absorption. Resistances on the other side of the surface barrier usually only affect the drug accumulation vs. time profile in the medium, but not the steady-state flux or absorption. The role of unstirred water layer adjacent to the internal capillary wall is postulated to play an important role in causing the blood-flow dependency in absorption, a phenomenon that cannot be rationalized by the conventional effective permeability concept. The conventional concept of sink conditions on the serosal side is questioned. The present analysis further supports the use of the absorptive or transport clearance concept in absorption or transport study. Effective permeability is regarded as a mathematical operator for transport across a barrier or a tissue, and may be unrelated to the Fick's law of diffusion under most conditions. The velocity unit for P is regarded simply as a "collapsed" unit based on the absorptive or transport clearance per unit gross surface area. It is hoped that this commentary will stimulate further research and discussions in this general area of drug transport and absorption. It appears that there is a need to experimentally confirm the total resistance theory in biological systems.