Effects of different absorption enhancers on the permeation of ebiratide, an ACTH analogue, across intestinal membranes.

The permeation of ebiratide (H-Met(O2)-Glu-His-Phe-D-Lys-Phe-NH(CH2)8NH2), a novel ACTH analogue, across the intestinal mucosae has been examined by use of isolated intestinal membranes from rats in a modified Ussing chamber. Regional differences were observed in the permeation of ebiratide across intestinal membranes; the order of membrane permeability was jejunum > ileum > duodenum > colon. Overall, the permeation of ebiratide was relatively poor. The effects of various absorption enhancers were examined to increase the intestinal permeability to ebiratide. Sodium glycocholate and sodium caprate had no significant enhancing effect on the permeability of the jejunal membrane, but significantly enhanced the permeation of ebiratide through the colonic membrane. On the other hand, N-dodecyl-beta-D-maltopyramoside (LM) significantly enhanced the permeation of ebiratide through both jejunal and colonic membranes. In general, the absorption-enhancing effects of these agents were more predominant in the colon than in the jejunum. Membrane damage by the absorption enhancers was evaluated by measuring the amount of protein released from the intestinal membrane. It was found that all the absorption enhancers slightly increased the amount of protein released, but that the amounts of protein released in the presence of these enhancers were much less than in the presence of ethylenediaminetetraacetic acid (EDTA), used as a positive control. These findings suggest that the absorption enhancers, especially LM might be useful adjuvants for improving the intestinal absorption of peptide and protein drugs, including ebiratide.