The in vivo gastrointestinal absorption in rats of the intact cyclo(L-leucylglycine) dipeptide

Abstract

Unanesthetized rats with catheterized portal veins were administered, intragastrically, a saline solution of the diketopiperazine cyclo(L-leucyl-[U-14C]glycine) (cyclo(L-Leu-[14C]Gly)) at a dose of 47.9 nmol. The appearance of this cyclic dipeptide in portal vein plasma was followed chromatographically using a microcolumn of Sephadex G-25 complexed with copper. Further identification was done by thin-layer chromatography. Net absorption was evaluated by the balance method. The intestinal site of maximal absorptive capacity for cyclo(L-Leu-[14C]Gly) was also investigated. The gastric emptying rate was 98% in 15 min. After intragastric administration, cyclo(L-Leu-[14C]Gly) was absorbed (peak at 2.5 min) into the portal vein. The balance method showed that the efficiency of absorption was 94% within the first 10 min and was completed after 20 min. This compound was absorbed intact and remained unmetabolized in the portal vein of the rat and seemed to be absorbed throughout the length of the small intestine. Shortly after administration (1- to 5-min period), the greatest absorption of the diketopiperazine occurred at the level of the duodenum; however, the absorption maximum appeared to move down the gut and after 10 min the highest uptake took place in the jejunum, but never seemed to reach the ileum to a significant degree. Only negligible amounts of the cyclic dipeptide were excreted with the feces. Cyclo(L-Leu-[14C]Gly) is thus an example of a low molecular weight peptide which is rapidly and completely absorbed, after its intragastric administration at low concentration and is enzymatically stable during the process of absorption. In vitro experiments determined that this peptide apparently traverses the intestinal wall passively and does not use the carrier-mediated mechanisms for linear peptides.