Evidence of stereoselective and segmental-dependant transport of chiral antidiabetic drug nateglinide along the rat small intestine: possible role of efflux transporters

The purpose of the study was to investigate whether efflux and stereoselective mechanisms play any role in the transport of nateglinide (NA) enantiomers in rat. The transport of individual enantiomers and racemate was studied with and without the presence of an inhibitor for P-glycoprotein and MRP2, verapamil using duodenal, jejunal, and ileal intestinal sacs prepared from rat intestine. The intestinal samples were analyzed by a validated chiral HPLC method. Generally, higher concentrations of R-NA and its S-enantiomer were observed when the racemate was administered compared to administration of the individual enantiomers. Transport of NA enantiomers when co-incubated with verapamil was increased in the ileum by twofold to threefold with corresponding decreased secretion by almost threefold, while little change in the duodenum and jejunum. The transport of NA from everted sac segments (basal-to-apical side, secretion) was higher than the transport from the normal sac segments (apical-to-basal side, absorption) indicated an involvement of efflux-mediated transport. It has been found that the transport of NA is stereoselective and also regioselective, i.e., R-NA displayed higher efflux than S-NA and it was higher in ileum than the duodenum and jejunum. This study will really pave the way to understand how efflux transporters influence the absorption of chiral compounds when moving across the gastrointestinal tract.