paracellular diffusion in caco2 cell monolayers effect of perturbation on the transport of hydrophilic compounds that vary in charge and size we applied the principles of molecularsizerestricted diffusion within a negative electrostatic field of force to follow the changes in the aqueous pore radius of tight junctions tjs induced by perturbants and the accompanying influence on the permeation of neutral urea and mannitol cationic methylamine and atenolol and anionic formate and lactate compounds that vary in size the perturbants included palmitoyldlcarnitine pc which opens tjs by an unknown caindependent mechanism and ethyleneglycolbisbetaaminoethyl ethernnnntetraacetic acid egta a ca chelator mass transfer resistances of the collagencoated filter support and the aqueous boundary layers were factored out to yield paracellular permeability coefficients pp as viewed from the pp values of urea and mannitol egta exhibited insignificant effects on pore size at low concentrations compared with control and then caused a dramatic opening of the tjs over a narrow concentration range 13514 mm the pp values for urea and mannitol remained constant at 14 mm egta however pc produced dosedependent responses from o to 015 mm that plateaued at 015 mm in general cations permeated the cellular tjs faster and anions slower than their neutral images the effects of changes in pore size 46 to 146 a in effective radius on the ability of these solutes to permeate the tjs were analyzed by the renkin molecular sieving function these studies established an experimental theoretical and quantitative template to assess perturbants of the tj and define the limits short of detrimental effects at which the tjs may be sufficiently perturbed for maximal enhancement of permeation of solutes varying in size and charge