MECHANISTIC STUDIES ON EFFERVESCENT-INDUCED PERMEABILITY ENHANCEMENT

Purpose. To determine the mechanism(s) by which effervescence induces penetration enhancement of a broad range of compounds ranging in size, structure, and other physiocochemical properties across rat and rabbi t small intestinal epithelium. Methods. Effervescent induced penetrati on enhancement was investigated in vitro by utilization of a modified Ussing chamber diffusion cell apparatus and in vivo by single-pass int estinal perfusion. Results. Carbon dioxide (CO2) bubbling directly ont o rabbit ileum epithelium induced an increase in drug permeability. Me chanistic studies indicated that effects due to CO2 bubble evolution, such as increased drug dissolution rates, mucus thinning/stripping, an d pH buffer effects did not contribute to increases in drug flux. Cell ular enzyme (5'-ND and LDH) and total protein release assays did not i ndicate cell membrane perturbation and/or damage. CO2 bubbling induced a reduction in transepithelial electrical resistance (TEER) indicatin g epithelial disruption due to a structural change of the paracellular pathway. This was further substantiated by a MW dependence on paracel lular marker flux. In addition, tissue recovery was relatively rapid, approximate to 20 min. Conclusions. CO2 bubbling directly onto the int estinal epithelium induced enhanced drug permeability due to an altera tion of the paracellular pathway. This, in addition to fluid flow and membrane hydrophobicity concepts may account for observed increases in drug flux.