PT  - JOURNAL ARTICLE
AU  - Ryuichi Ohgaki
AU  - Ling Wei
AU  - Kazunori Yamada
AU  - Taiki Hara
AU  - Chiaki Kuriyama
AU  - Suguru Okuda
AU  - Kiichiro Ueta
AU  - Masaharu Shiotani
AU  - Shushi Nagamori
AU  - Yoshikatsu Kanai
TI  - Interaction of the sodium/glucose cotransporter (SGLT) 2 inhibitor canagliflozin with SGLT1 and SGLT2: inhibition kinetics, sidedness of action, and transporter-associated incorporation accounting for its pharmacodynamic and pharmacokinetic features
AID  - 10.1124/jpet.116.232025
DP  - 2016 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.116.232025
4099  - http://jpet.aspetjournals.org/content/early/2016/04/27/jpet.116.232025.short
4100  - http://jpet.aspetjournals.org/content/early/2016/04/27/jpet.116.232025.full
AB  - 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 nM 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.