Effects of surfactant-based permeation enhancers on mannitol permeability, histology, and electrogenic ion transport responses in excised rat colonic mucosae

Surfactant-based intestinal permeation enhancers (PEs) are constituents of several oral macromolecule formulations in clinical trials. This study examined the interaction of a test panel of surfactant-based PEs with isolated rat colonic mucosae mounted in Ussing chambers in an attempt to determine if increases in transepithelial permeability can be separated from induction of mucosal perturbation. The aim was to assess the effects of PEs on (i) apparent permeability coefficient (P-app) of [C-14]-mannitol (ii) histology score and (iii) short-circuit current (Delta I-sc) responses to a cholinomimetic (carbachol, CCh). Enhancement ratio increases for P-app values followed the order: C-10 > C-9 = C-11:1 > a bile salt blend > sodium choleate > sucrose laurate > Labrasol (R) > C12E8 > C-12 > Cremophor (R) A25 > C-7 > sucrose stearate > Kolliphor (R) HS15 > Kolliphor (R) TPGS. Exposures that increased the P-app by >= 2-fold over 120 min were accompanied by histological damage in 94% of tissues, and by a decreased Delta I-sc response to CCh in 83%. A degree of separation between the increased P-app of [C-14]-mannitol and histological damage and diminution of the Delta I-sc response to CCh was observed at selected concentrations of Labrasol (R). Overall, this surfactant-based PE selection caused transcellular perturbation at similar concentrations to those that enhanced permeability.