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. 14C-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.
- Received January 12, 2016.
- Accepted April 26, 2016.
R.O. and L.W. contributed equally to this work.
This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science; the Ministry of Education, Science, Culture, Sports and Technology of Japan (MEXT); and the Mitsubishi Tanabe Pharma Corporation. L.W. was supported by a scholarship from MEXT for foreign students.
This work was previously presented in part as follows: L.W., R.O., S.N., and Y.K. Interaction of a novel SGLT2 inhibitor Canagliflozin with human SGLT2. The 57th Annual Meeting of the Japan Diabetes Society, 2014 May 22–24; Osaka, Japan; and R.O., L.W., S.N., K.Y., T.H., C.K., K.U., M.S., and Y.K. Study on the transport of SGLT2 inhibitor canagliflozin by human SGLT2 and its inhibitory action from extracellular and intracellular sides. The 58th Annual Meeting of the Japan Diabetes Society, 2015 May 21–24; Fukuoka, Japan.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics