THE RELATIONSHIP BETWEEN RAT INTESTINAL PERMEABILITY AND HYDROPHILIC PROBE SIZE

Purpose. The relationship between rat intestinal permeability (P-app) of a range of hydrophilic probe molecules and probe geometry was exami ned. Methods. Molecules studied included mannitol, the polyethylene gl ycols (PEGs) 400, 900, and 4000, the dextran conjugated dye Texas Red( R) (MW 3000) and the polysaccharide inulin (MW 5500). Molecular surfac e area, volume and cross-sectional diameter for each probe were determ ined from computer models. The effect of the bile salt sodium cholate, and bile salt: fatty acid mixed micelles on probe intestinal permeabi lity was also studied. Results. Of the size parameters tested, cross-s ectional diameter correlated best with log intestinal permeability. Th e data was fitted to a relationship of the form P-app = P-app(0) exp(- Kr-ca) where r(ca) is the molecular cross sectional radius, P-app(0) a nd K are constants. Estimates of equivalent pore radii (R) were also m ade; the use of r(ca) giving the most reasonable estimate of R. Absorp tion of all probes was enhanced by both simple and mixed micellar syst ems. Conclusions. For large hydrophilic probes, and possibly protein d rugs, cross sectional diameter is a more important size parameter than volume based values for evaluating size-related retarded absorption. The relationship established may be used as a tool to assess absorptio n enhancement potential of excipients.