Ohgaki Ryuichi, Wei Ling, Yamada Kazunori, Hara Taiki, Kuriyama Chiaki, Okuda Suguru, Ueta Kiichiro, Shiotani Masaharu, Nagamori Shushi, Kanai Yoshikatsu
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.).
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.)
J Pharmacol Exp Ther. 2016 Jul;358(1):94-102. doi: 10.1124/jpet.116.232025. Epub 2016 Apr 27.
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.
卡格列净是一种选择性钠/葡萄糖共转运蛋白（SGLT）2抑制剂，可抑制2型糖尿病患者肾脏对葡萄糖的重吸收并降低血糖水平。卡格列净的一个特点是在临床剂量下对肠道中的SGLT1有适度的抑制作用。为揭示其作用机制，我们研究了卡格列净与SGLT1和SGLT2的相互作用。在表达人SGLT1或SGLT2的细胞中检测了抑制动力学和转运体介导的摄取。进行全细胞膜片钳记录以检测药物作用的方向性。卡格列净竞争性抑制SGLT1和SGLT2，对SGLT2具有高效力和选择性。SGLT1和SGLT2的抑制常数（Ki）值分别为770.5和4.0 nM。（14）C-卡格列净被认为可由SGLT2转运；然而，转运速率低于α-甲基-D-吡喃葡萄糖苷。卡格列净优先从细胞外侧而非细胞内侧抑制α-甲基-D-吡喃葡萄糖苷诱导的SGLT1和SGLT2介导的内向电流。根据Ki值，估计卡格列净可从肾近端小管的尿侧充分抑制SGLT2。SGLT1的Ki值表明，考虑到血浆中未结合卡格列净的最大浓度，卡格列净从肠腔侧抑制小肠中的SGLT1，而不影响心脏和骨骼肌中的SGLT1。同样，肾脏中的SGLT1也不会被抑制，从而有助于预防低血糖。与SGLT2结合后，卡格列净可能会被SGLT2重吸收，这导致卡格列净的尿排泄率低且药物作用时间延长。
