title: Improved intestinal membrane permeability of hexose-quinoline derivatives via the hexose transporter, SGLT1.
abstract: Intestinal membrane permeability is an important factor affecting the bioavailability of drugs. As a strategy to improve membrane permeability, membrane transporters are useful targets since essential nutrients are absorbed efficiently via specific transporters. For example, there are reports that intestinal hexose transporters could be used as a tool to improve permeability; however, there has been no direct evidence that the transporter protein, sodium/glucose cotransporter 1 (SGLT1), is involved in the transport of hexose analogs. Accordingly, we examined directly whether the intestinal membrane permeability of hexose analogs can be improved by utilizing SGLT1. Three hexose-quinoline derivatives were synthesized and their interactions with SGLT1 were evaluated. Among the three derivatives, the glucose-quinoline molecule exhibited an inhibitory effect on D-glucose uptake by both rat intestinal brush-border membrane vesicles (BBMVs) and Xenopus oocytes expressing SGLT1. In addition, significant uptake of the glucose-quinoline derivative by Xenopus oocytes expressing SGLT1 was observed by both an electrophysiological assay and direct measurement of the uptake of the compound, while the galactose-quinoline derivative did not show significant uptake via SGLT1. Thus, it was directly demonstrated that SGLT1 could be used as a tool for the improvement of intestinal membrane permeability of drugs by modification to the glucose analogs.
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan.
authors.forename: Katsumasa
authors.initials: K
authors.lastname: Otake
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Ryunosuke
authors.initials: R
authors.lastname: Higashi
authors.forename: Hikaru
authors.initials: H
authors.lastname: Yabuuchi
authors.forename: Makoto
authors.initials: M
authors.lastname: Haga
authors.forename: Tomoji
authors.initials: T
authors.lastname: Maeda
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Cook
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
mesh_terms: D000818:Animals; D001692:Biological Transport; D005947:Glucose / Q000378:metabolism; D006601:Hexoses / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D010539:Permeability; D011804:Quinolines / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D051269:Sodium-Glucose Transporter 1 / Q000502:physiology*; D014981:Xenopus