Intestinal Drug Absorption and Excretion-Detoxication Using Regulation of Membrane Permeation by Oligopeptide-produced Neutrophils

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Formyl-methionyl-leucyl-phenylalanine which is produced by bacteria stimulates neutrophils and enlarges paracellular pathway, tight junction (TJ), suggesting that the oligopeptide can be an endogenous absorption enhancer. In the first year, we examined the enhancing action of the active oxygen compound which is produced by neutrophils, hydrogen peroxide, using changes in permeability (Pm) of the paracellular permeant compounds, FITC-dextran 4000 (FD-4) and the transepithelial electric resistance (Rm) in rat jejunum, ileum and colon.Hydrogen peroxide reduces Rm and increases Pm in all absorption sites, indicating the enlargement of TJ.These actions are remarkable in jejunum and ileum, and greater in the mucosal side than in the serosal side. In addition to hydrogen peroxide, O_2^- and OH^- were found to participate the TJ opening mechanism.In the second year, the effects of hydrogen peroxide were examined using human colon adrenocarcinoma (Caco-2). Also in Caco-2 cells, hydrogen peroxide decreases Rm and the action is more remarkable in the apical side than in the basal side, indicating that hydrogen peroxide has the same action in Caco-2 and the rat intestine. Further, the effects of hydrogen peroxide on the transcellular pathway were examined from the functional changes in P-glycoprotein (P-gp) which has the secretory action of the substrates from the cell to lumen. The transport of Rhodamine 123, which is a substrate of P-gp, from mucosal to serosal direction was increased but that of the reverse direction was decreased, indicating the reduction of P-gp function.The analysis of production process of hydrogen peroxide by neutrophils, the participation of immunological cell, and the application of oligopeptide to the oral dosage formulation remained to be unresolved.