title: 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.
abstract: 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 beta-lactam antibiotic, cefixime, and alpha-methyl-d-glycopyranoside (alpha-MDG), respectively, using rab8 gene knockout [rab8(-/-)] mice as experimental animals deficient in those transporters. Plasma concentration of cefixime and alpha-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 alpha-MDG, respectively, in vivo in mice. The present findings also illustrate the pharmacokinetic influence of the sorting machinery protein Rab8.
authors.affiliation: Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kato
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sugiura
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Nakadera
authors.forename: Mikihiro
authors.initials: M
authors.lastname: Sugiura
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kubo
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.forename: Akihiro
authors.initials: A
authors.lastname: Harada
authors.forename: Akira
authors.initials: A
authors.lastname: Tsuji
mesh_terms: D000818:Animals; D020682:Cefixime / Q000493:pharmacokinetics*; D005260:Female; D007408:Intestinal Absorption / Q000502:physiology*; D007421:Intestine, Small / Q000378:metabolism; D008297:Male; D008757:Methylglucosides / Q000493:pharmacokinetics*; D051379:Mice; D018345:Mice, Knockout; D000074011:Peptide Transporter 1; D051269:Sodium-Glucose Transporter 1 / Q000502:physiology*; D027981:Symporters / Q000502:physiology*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D008757:Methylglucosides; D000074011:Peptide Transporter 1; C521976:Rab8 protein, mouse; C489941:Slc15a1 protein, mouse; C495675:Slc5a1 protein, mouse; D051269:Sodium-Glucose Transporter 1; D027981:Symporters; D020682:Cefixime; D020691:rab GTP-Binding Proteins