title: Concentration-dependent preferences of absorptive and excretive transport cause atypical intestinal absorption of cyclic phenylalanylserine: small intestine acts as an interface between the body and ingested compounds.
abstract: Intestinal absorption of cyclic phenylalanylserine (cyclo(Phe-Ser)), a precursor of gliotoxin, was studied in isolated rat small intestine as a model cyclic dipeptide. Absorption clearance (CLabs) decreased in the presence of glycylsarcosine, cephalexin or cephradine, substrates for H+/oligopeptide cotransporter (PEPT1). CLabs of cyclo(Phe-Ser) also decreased at 4 degrees C. These indicate that cyclo(Phe-Ser) is in part transported by PEPT1. However, Eadie-Hofstee plot of absorption revealed an atypical profile at lower concentrations of cyclo(Phe-Ser) (around 0.1 mM). Moreover, comparative experiments of absorptive and excretive transport showed that excretive transport from the serosal to mucosal side of isolated intestinal tissue at a 0.1 mM cyclo(Phe-Ser) was superior to absorptive transport from the mucosal side to the serosal side, and vise versa at a 1 mM cyclo(Phe-Ser). These results as well as the results of kinetic analysis indicate that intestinal absorption consists of passive transport, carrier-mediated absorptive transport by PEPT1 and carrier-mediated excretive transport, resulting in atypical absorption. Although cyclic dipeptides have potentials for drug, their intestinal absorption may be complex. The results of this study lead us conclude that absorptive and excretive transport by the small intestine acts as an interface between the body and ingested compounds.
authors.affiliation: Department of Biopharmaceutics and Drug Rational Research Center School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. mizuma@ps.toyaku.ac.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Mizuma
authors.forename: Takuo
authors.initials: T
authors.lastname: Narasaka
authors.forename: Wakako
authors.initials: W
authors.lastname: Hiyoshi
authors.forename: Shoji
authors.initials: S
authors.lastname: Awazu
mesh_terms: D000465:Algorithms; D000818:Animals; D001693:Biological Transport, Active / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D002506:Cephalexin / Q000493:pharmacokinetics; D002511:Cephalosporins / Q000493:pharmacokinetics; D002515:Cephradine / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D004151:Dipeptides / Q000378:metabolism / Q000493:pharmacokinetics*; D007408:Intestinal Absorption / Q000502:physiology*; D007421:Intestine, Small / Q000378:metabolism*; D008297:Male; D000074011:Peptide Transporter 1; D051381:Rats; D017208:Rats, Wistar; D027981:Symporters
chemical_list: D002352:Carrier Proteins; D002511:Cephalosporins; D004151:Dipeptides; D000074011:Peptide Transporter 1; C489940:Slc15a1 protein, rat; D027981:Symporters; C025275:phenylalanylserine; D002515:Cephradine; D002506:Cephalexin