title: Interaction of the Sodium/Glucose Cotransporter (SGLT) 2 inhibitor Canagliflozin with SGLT1 and SGLT2.
abstract: Canagliflozin, a selective sodium/glucose cotransporter (SGLT) 2 inhibitor, suppresses the renal reabsorption of glucose and decreases blood glucose level in patients with type 2 diabetes. A characteristic of canagliflozin is its modest SGLT1 inhibitory action in the intestine at clinical dosage. To reveal its mechanism of action, we investigated the interaction of canagliflozin with SGLT1 and SGLT2. Inhibition kinetics and transporter-mediated uptake were examined in human SGLT1- or SGLT2-expressing cells. Whole-cell patch-clamp recording was conducted to examine the sidedness of drug action. Canagliflozin competitively inhibited SGLT1 and SGLT2, with high potency and selectivity for SGLT2. Inhibition constant (Ki) values for SGLT1 and SGLT2 were 770.5 and 4.0 nM, respectively. (14)C-canagliflozin was suggested to be transported by SGLT2; however, the transport rate was less than that of α-methyl-d-glucopyranoside. Canagliflozin inhibited α-methyl-d-glucopyranoside-induced SGLT1- and SGLT2-mediated inward currents preferentially from the extracellular side and not from the intracellular side. Based on the Ki value, canagliflozin is estimated to sufficiently inhibit SGLT2 from the urinary side in renal proximal tubules. The Ki value for SGLT1 suggests that canagliflozin suppresses SGLT1 in the small intestine from the luminal side, whereas it does not affect SGLT1 in the heart and skeletal muscle, considering the maximal concentration of plasma-unbound canagliflozin. Similarly, SGLT1 in the kidney would not be inhibited, thereby aiding in the prevention of hypoglycemia. After binding to SGLT2, canagliflozin may be reabsorbed by SGLT2, which leads to the low urinary excretion and prolonged drug action of canagliflozin.
authors.affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan (R.O., L.W., S.O., S.N., Y.K.); and Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (K.Y., T.H., C.K., K.U., M.S.).
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Ohgaki
authors.affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan (R.O., L.W., S.O., S.N., Y.K.); and Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (K.Y., T.H., C.K., K.U., M.S.).
authors.forename: Ling
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan (R.O., L.W., S.O., S.N., Y.K.); and Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (K.Y., T.H., C.K., K.U., M.S.).
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan (R.O., L.W., S.O., S.N., Y.K.); and Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (K.Y., T.H., C.K., K.U., M.S.).
authors.forename: Taiki
authors.initials: T
authors.lastname: Hara
authors.affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan (R.O., L.W., S.O., S.N., Y.K.); and Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (K.Y., T.H., C.K., K.U., M.S.).
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kuriyama
authors.affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan (R.O., L.W., S.O., S.N., Y.K.); and Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (K.Y., T.H., C.K., K.U., M.S.).
authors.forename: Suguru
authors.initials: S
authors.lastname: Okuda
authors.affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan (R.O., L.W., S.O., S.N., Y.K.); and Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (K.Y., T.H., C.K., K.U., M.S.).
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Ueta
authors.affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan (R.O., L.W., S.O., S.N., Y.K.); and Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (K.Y., T.H., C.K., K.U., M.S.).
authors.forename: Masaharu
authors.initials: M
authors.lastname: Shiotani
authors.affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan (R.O., L.W., S.O., S.N., Y.K.); and Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (K.Y., T.H., C.K., K.U., M.S.).
authors.forename: Shushi
authors.initials: S
authors.lastname: Nagamori
authors.affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan (R.O., L.W., S.O., S.N., Y.K.); and Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (K.Y., T.H., C.K., K.U., M.S.) ykanai@pharma1.med.osaka-u.ac.jp.
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Kanai
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D000068896:Canagliflozin / Q000378:metabolism / Q000494:pharmacology*; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D018408:Patch-Clamp Techniques; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D051297:Sodium-Glucose Transporter 2 / Q000235:genetics; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D014162:Transfection
chemical_list: D007004:Hypoglycemic Agents; C495674:SLC5A1 protein, human; C089180:SLC5A2 protein, human; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000068896:Canagliflozin