title: Inhibitory effect of novel oral hypoglycemic agent nateglinide (AY4166) on peptide transporters PEPT1 and PEPT2.
abstract: The novel oral hypoglycemic agent nateglinide (AY4166) is a nonsulfonylurea insulin secretagogue, and its pharmacokinetic features include rapid absorption and elimination. As nateglinide is a dipeptide-like drug, we investigated the interaction of nateglinide with peptide transporters PEPT1 and PEPT2, which mediate the absorption of various peptide-like drugs. Nateglinide exhibited a potent inhibitory effect on [14C]glycylsarcosine uptake by the human colon adenocarcinoma cell line Caco-2 and rat PEPT-transfectants. Kinetic analysis revealed that these inhibitory effects were noncompetitive. Na(+)-coupled alanine or threonine uptake by Caco-2 cells was not inhibited by nateglinide, suggesting that the inhibitory effect of nateglinide on peptide transporters was not due to nonspecific interaction. There was little uptake of [14C]nateglinide by peptide transporters. Various sulfonylureas, such as glibenclamide, also inhibited [14C]glycylsarcosine uptake by rat PEPT-transfectants. In conclusion, nateglinide as well as sulfonylureas inhibit the transport activity of PEPT1 and PEPT2, although nateglinide itself is not transported by these transporters.
authors.affiliation: Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Terada
authors.forename: K
authors.initials: K
authors.lastname: Sawada
authors.forename: H
authors.initials: H
authors.lastname: Saito
authors.forename: Y
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: K
authors.initials: K
authors.lastname: Inui
mesh_terms: D000284:Administration, Oral; D000409:Alanine / Q000378:metabolism; D000818:Animals; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D003510:Cyclohexanes / Q000493:pharmacokinetics / Q000494:pharmacology*; D004151:Dipeptides / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007700:Kinetics; D000077715:Nateglinide; D000074011:Peptide Transporter 1; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D027981:Symporters; D013912:Threonine / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D003510:Cyclohexanes; D004151:Dipeptides; D007004:Hypoglycemic Agents; D000074011:Peptide Transporter 1; C082186:SLC15A1 protein, human; C489940:Slc15a1 protein, rat; D027981:Symporters; C093694:hydrogen-coupled oligopeptide transporter PepT2; C004194:glycylsarcosine; D013912:Threonine; D000077715:Nateglinide; D010649:Phenylalanine; D000409:Alanine