title: Carboxyl group-terminated polyamidoamine dendrimers bearing glucosides inhibit intestinal hexose transporter-mediated D-glucose uptake.
abstract: We are investigating non-absorbable polymeric conjugates bearing glucosides via a omega-amino triethylene glycol linker as oral anti-diabetic drugs that suppress an increase in the blood glucose level after meals through inhibition of Na(+)/glucose cotransporter (SGLT1). When the linker was bound to phloridzin, which is a SGLT1 inhibitor, to yield a precursor of the conjugate, the in vitro inhibitory effect on SGLT1-mediated d-glucose uptake was reduced to about one-tenth that of phloridzin. The inhibitory effect was recovered completely when the precursor was immobilized on the surface of poly(amidoamine) (PAMAM) dendrimers (generation: 3.0) by coupling with one-eighth or less of the terminal carboxyl groups. We considered that the phloridzin-derived glucose moiety on the dendrimer surface was prerequisite for SGLT1 inhibition but that the aglycon part was not always required for the inhibition. Commercially used arbutin, a SGLT1 substrate, was substituted for phloridzin whose aglycon is composed of toxic phloretin. The in vitro inhibitory effect of arbutin was about one-thirtieth that of intact phloridzin; however, the inhibitory effect of the PAMAM dendrimer-arbutin conjugates was as strong as that of the PAMAM dendrimer-phloridzin conjugates. Rat experiments further showed that the PAMAM dendrimer-arbutin conjugates significantly suppressed d-glucose-induced hyperglycemic effects. The dendritic conjugate bearing arbutin appears to be a good candidate as an oral anti-diabetic drug.
authors.affiliation: Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan. sakuma@pharm.setsunan.ac.jp
authors.forename: Shinji
authors.initials: S
authors.lastname: Sakuma
authors.forename: Yumi
authors.initials: Y
authors.lastname: Teraoka
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Sagawa
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Masaoka
authors.forename: Makoto
authors.initials: M
authors.lastname: Kataoka
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamashita
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Shirasaka
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ikumi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kida
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Akashi
mesh_terms: D000818:Animals; D050091:Dendrimers / Q000737:chemistry*; D005947:Glucose / Q000378:metabolism*; D005960:Glucosides / Q000737:chemistry*; D007413:Intestinal Mucosa / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: D050091:Dendrimers; D005960:Glucosides; D009004:Monosaccharide Transport Proteins; C104700:PAMAM Starburst; D005947:Glucose