Sodium glucose co-transporter 2 (SGLT2) is a high-capacity glucose transporter mediating the majority of the glucose resorption in kidney. Canagliflozin hemihydrate is a selective, potent SGLT2 inhibitor with IC50 values of 4.4, 3.7, and 2.0 nM for human SGLT2, rat SGLT2, and mouse SGLT2, respectively. In contrast, canagliflozin hemihydrate inhibited human, rat and mouse SGLT1 with IC50 values of 684, 571, and >1000 nM, respectively. In L6 myoblasts, canagliflozin hemihydrate at 10 μM blocked the non-Na+-linked GLUT-mediated 3H-2-DG uptake by < 50%. Canagliflozin hemihydrate at 10 μM inhibited DNJ-induced currents by 23.4% in SGLT3-injected oocytes, whereas the same treatment of canagliflozin hemihydrate had no effect on currents in water-injected oocytes. In Zucker diabetic fatty (ZDF) rats treated by 1 mg/kg canagliflozin hemihydrate, renal threshold for glucose excretion was reduced from 415 mg/dl to 94 mg/dl at 90 min post treatment. In db/db mice, single dose of canagliflozin hemihydrate (1 and 10 mg/kg) rapidly downregulated non-fasting blood glucose concentration in a dose-dependent manner at 1h post treatment. When ZDF rats were treated with canagliflozin hemihydrate at different doses (3, 10, or 30 mg/kg) for 4 weeks, the non-fasting blood glucose and the level of HbA1c were decreased in all canagliflozin hemihydrate-treated rats compared to control group. Decreased blood glucose level following an oral glucose tolerance test was also observed in canagliflozin hemihydrate-treated rats. Treatment of 30 mg/kg canagliflozin hemihydrate in DIO mice for 4 weeks decreased their blood glucose level, respiratory exchange ratio, and body weight gain compared to vehicle-treated mice[1].
作用机制
Canagliflozin hemihydrate is a potent, selective inhibitor of SGLT2 that downregulates the renal glucose resorptive capacity, induces urinary glucose excretion, improves glycemic control and beta-cell function in vivo[1].
搜索
