Enhanced Permeability of Phenylalanyl-glycine (Phe-Gly) Across the Intestinal Membranes by Chemical Modification with Various Fatty Acids

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We synthesized four novel lipophilic derivatives of phenylalanyl-glycine (Phe-Gly), C4-Phe-Gly, Phe-Gly-C4, C6-Phe-Gly and C8-Phe-Gly by chemical modification with butyric acid (C4), caproic acid (C6) and octanoic acid (C8). The effect of the acylation on the stability, permeability and accumulation of Phe-Gly in the intestine was investigated by in vitro studies. The stability of Phe-Gly in homogenates of duodenal and colonic membranes was low, but was significantly improved by the acylation except for Phe-Gly-C4. In the transport studies, a modified Ussing chamber was used for the intestinal permeability experiments with Phe-Gly and its acyl derivatives. The permeability of native Phe-Gly and Phe-Gly-C4 across the intestinal membrane was not observed during the transport studies. However, the permeability of Phe-Gly was much improved by chemical modification with various fatty acids to its N-terminal portion. The permeability of acyl-Phe-Gly derivatives across the intestinal membrane decreased with increasing the chain length of fatty acids. In addition, the intestinal tissue accumulation of acyl-Phe-Gly derivatives at the end of the transport studies was much higher than that of native Phe-Gly. The intestinal tissue accumulation of acyl-Phe-Gly in the duodenum increased as the chain length of fatty acids increased. Furthermore, intestinal permeability of C4-Phe-Gly was slightly inhibited in the presence of 5 mM ceftibuten and was significantly reduced under low temperature condition. We observed a directional difference in the transport of C4-Phe-Gly (the mucosal to serosal transport of C4-Phe-Gly was higher than its serosal to mucosal transport) suggesting that C4-Phe-Gly might be transported by a carrier-mediated process as well as other dipeptides. These findings indicate that acylation might be useful approach to enhance the transport of Phe-Gly, a model dipeptide, transported by a carrier-mediated process.