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
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
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DOI：
10.1124/jpet.116.232025
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发表时间：
2016-07-01
影响因子：
3.5
通讯作者：
Kanai, Yoshikatsu
中科院分区：
文献类型：
--
作者：
Ohgaki, Ryuichi;Wei, Ling;Kanai, Yoshikatsu
Canagliflozin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在肠道中具有适度的SGLT1抑制作用。为了揭示其作用机制，我们研究了卡格列净与SGLT1和SGLT2的相互作用。在人SGLT1-或sglt2表达细胞中检测了抑制动力学和转运体介导的摄取。采用全细胞膜片钳记录，观察药物作用的侧边性。Canagliflozin竞争性地抑制SGLT1和SGLT2，对SGLT2具有高效力和选择性。SGLT1和SGLT2的抑制常数（K-i）分别为770.5 nM和4.0 nM。C-14-canagliflozin被认为是由SGLT2运输的；但转运率低于α -甲基- d -葡萄糖吡喃苷。卡格列净抑制α -甲基- d -葡萄糖吡喃苷诱导的SGLT1-和sglt2介导的细胞外电流，而不是细胞内电流。根据K-i值，估计卡格列净可以充分抑制肾近端小管尿侧的SGLT2。SGLT1的Ki值表明，考虑到血浆未结合卡格列净的最大浓度，卡格列净从管腔侧抑制小肠的SGLT1，而不影响心脏和骨骼肌的SGLT1。同样，肾脏中的SGLT1不会被抑制，从而有助于预防低血糖。卡格列净与SGLT2结合后，可能会被SGLT2重吸收，导致尿排泄量减少，延长卡格列净的药物作用。
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 (K-i) values for SGLT1 and SGLT2 were 770.5 and 4.0 nM, respectively. C-14-canagliflozin was suggested to be transported by SGLT2; however, the transport rate was less than that of alpha-methyl-D-glucopyranoside. Canagliflozin inhibited alpha-methyl-D-glucopyranoside-induced SGLT1- and SGLT2-mediated inward currents preferentially from the extracellular side and not from the intracellular side. Based on the K-i 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.