生物活性

• 靶点	SGLT2 IC50:2.2nM

• 描述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].

• 动物研究
  剂量	Rat: 10 mg/kg - 30 mg/kg[2] (p.o.); 3 mg/kg[2] (i.v.)
  给药途径	p..o., i.v.
  动物药代数据	Animal Rats[2] Dose 3 mg/kg (i.v.) 10 mg/kg (p.o.) Administration i.v. p.o. F 85% (p.o.) CLtot 236 ml/h/kg (i.v.) T1/2 5.0 h (i.v.) 5.2 h (p.o.) Tmax 5.0 h (p.o.) AUC0-inf 12703 ng·h/ml (i.v.) 35980 ng·h/ml (p.o.) Cmax 2513 ng/ml (p.o.) Vdss 1357 ml/kg (i.v.)