title: Stabilization of enzyme-susceptible glucoside bonds of phloridzin through conjugation with poly(gamma-glutamic acid).
abstract: We designed and prepared poly(gamma-glutamic acid)s (gamma-PGA) bearing phloridzin, which is an inhibitor of Na(+)/glucose cotransporter 1 (SGLT1), via a non-biodegradable omega-amino triethylene glycol linker. Properties of gamma-PGA-phloridzin conjugates (PGA-PRZ) were examined because our previous research revealed that PGA-PRZ with a 15% phloridzin content suppressed an increase in the blood glucose level after oral administration of D-glucose in rats, even though intact phloridzin scarcely affected the glucose-induced hyperglycemic effect. In uptake experiments using rat small intestinal brush-border membrane vesicles (BBMVs), the conjugation resulted in a 10-fold increase in the inhibitor concentration giving half-maximum inhibition of SGLT1-mediated D-glucose uptake, indicating that the inhibitory effect on the uptake was considerably reduced. On the other hand, beta-glucosidase-susceptible glucoside bonds of phloridzin were stabilized through conjugation with gamma-PGA. D-glucose, which is essential for the inhibition of SGLT1, was not released from PGA-PRZ with a phloridzin content of greater than 15% incubated with BBMVs, despite the immediate release of D-glucose from intact phloridzin. It was strongly indicated that the improved stability resulted in the difference in pharmacological activities between the conjugate and phloridzin. We also concluded that the toxic phloretin was not released from the conjugates. These results suggest that gamma-PGA-phloridzin conjugates have potential as oral anti-diabetic drugs with high safety.
authors.affiliation: Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan. sakuma@pharm.setsunan.ac.jp
authors.forename: Shinji
authors.initials: S
authors.lastname: Sakuma
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; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D005947:Glucose / Q000378:metabolism; D005960:Glucosides / Q000737:chemistry*; D006207:Half-Life; D006801:Humans; D008297:Male; D008855:Microscopy, Electron, Scanning; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010316:Particle Size; D010695:Phlorhizin / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry; D011099:Polyglutamic Acid / Q000737:chemistry*; D018075:RNA, Complementary / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D005960:Glucosides; D018075:RNA, Complementary; C495674:SLC5A1 protein, human; D051269:Sodium-Glucose Transporter 1; D011099:Polyglutamic Acid; C028914:triethylene glycol; D011092:Polyethylene Glycols; D010695:Phlorhizin; D005947:Glucose