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Investigation of the Role of Oligopeptide Transporter PEPT1 and Sodium/Glucose Cotransporter SGLT1 in Intestinal Absorption of Their Substrates Using Small GTP-Binding Protein Rab8-Null Mice

Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakumamachi, Kanazawa, Japan (Y.Ka., T.S., Y.N., M.S., Y.Ku., A.T.); and Laboratory of Molecular Traffic, Department of Molecular and Cellular Biology, Institute for Molecular and Cellular Regulation, Gumma University, Showa, Maebashi, Gunma, Japan (T.S., A.H.)

A small GTP-binding protein, Rab8, is essential for apical localization of oligopeptide transporter PEPT1/SLC15A1 and sodium/glucose cotransporter SGLT1/SLC5A1 in small intestine; deficiency of rab8 gene results in mislocalization and reduced expression of these transporters. Here, we examined the role of PEPT1 and SGLT1 in vivo in gastrointestinal absorption of a β-lactam antibiotic, cefixime, and -methyl-d-glycopyranoside (-MDG), respectively, using rab8 gene knockout [rab8(–/–)] mice as experimental animals deficient in those transporters. Plasma concentration of cefixime and -MDG after oral administration in rab8(–/–) mice was much lower than that in wild-type mice, whereas such reduction in oral absorption was not observed for antipyrine, membrane permeation of which is not transporter-mediated. Uptake of cefixime from the apical side of isolated small intestine assessed by means of the everted sac method in wild-type mice was decreased in the presence of excess unlabeled glycylsarcosine, a PEPT1 substrate. In contrast, the uptake in rab8(–/–) mice was much lower than that in wild-type mice and comparable with that of an extracellular marker, mannitol, suggesting that the apical membrane permeability of cefixime was reduced in rab8(–/–) mice. Uptake of cefixime in wild-type mice was pH-dependent, being higher at lower pH, whereas that in rab8(–/–) mice remained at the background level at all pH values examined. These results suggest that PEPT1 and SGLT1 play an important role in gastrointestinal absorption of cefixime and -MDG, respectively, in vivo in mice. The present findings also illustrate the pharmacokinetic influence of the sorting machinery protein Rab8.