The absorption, especially the stability and transportability, of the cyclic peptide cyclic glycylphenylalanine (cyclo(Gly-Phe)) and the linear peptides glycylphenylalanine, glycyl-D-phenylalanine and phenylalanylglycine have been studied in rat small intestine. Linear peptides were degraded on the mucosal side and only glycyl-D-phenylalanine appeared on the serosal side. However, cyclo(Gly-Phe) was stable on the mucosal side and appeared on the serosal side. Furthermore, the absorption clearance of cyclo(Gly-Phe) was higher than that of glycyl-D-phenylalanine. In the presence of the peptidase inhibitor bestatin, the degradation of linear peptides was reduced and linear peptides appeared on the serosal side, but only phenylalanylglycine, which is transported by the oligopeptide transporter, was absorbed faster than cyclo(Gly-Phe). The absorption clearance of cyclo(Gly-Phe) was reduced as its concentration was increased from 125 microM to 500 microM. Furthermore, the absorption clearance of cyclo(Gly-Phe) at 125 microM was reduced at 4 degrees C or in the presence of glycylsarcosine and cephalexin, which are transported by the oligopeptide transporter. These results indicated that cyclo(Gly-Phe) was stable enough to be absorbed and was transported in part by the oligopeptide transporter rather than completely by passive diffusion.