H+-dependent transport mechanism of nateglinide in the brush-border membrane of the rat intestine.

(-)-N-(trans-4-Isopropylcyclohexanecarbonyl)-D-phenylalanine (nateglinide) is a novel oral hypoglycemic agent possessing a carboxyl group and a peptide-type bond in its structure. Although nateglinide quickly reaches the maximal serum concentration after oral administration, nateglinide itself is not transported by PepT1 or MCT1. The aim of this study was to characterize the transporters on the apical side of the small intestine that are responsible for the rapid absorption of nateglinide. The uptake of nateglinide by rat intestinal brush-border membrane vesicles is associated with a proton-coupled transport system. Ceftibuten competitively inhibited H(+)-dependent nateglinide uptake. Glycylsarcosine (Gly-Sar), cephradine, and cephalexin did not significantly inhibit the uptake of nateglinide. The combination of Gly-Sar and nateglinide greatly reduced the uptake of ceftibuten. The effect of the combined treatment was significantly greater than that of Gly-Sar alone. Furthermore, nateglinide competitively inhibited H(+)-driven ceftibuten transporter-mediated ceftibuten uptake. Ceftibuten transport occurs via at least two H(+)-dependent transport systems: one is PepT1, and the other is the ceftibuten/H(+) cotransport system. On the other hand, we demonstrated that nateglinide transport occurs via a single system that is H(+) dependent but is distinct from PepT1 and may be identical to the ceftibuten/H(+) cotransport system.