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].
Canagliflozin hemihydrate/坎格列净半水合物 细胞实验
Cell Line
Concentration
Treated Time
Description
References
J774A.1 cells
10 µM
1 hour
To evaluate the effect of CANA on LPS and nigericin-induced pyroptosis in J774A.1 cells, the results showed that CANA significantly reduced the expression of pyroptosis-related proteins.
Hepatol Commun. 2023 Feb 9;7(3):e0045.
AML12 cells
40 µM
24 hours
To evaluate the effect of CANA on FFA-induced steatosis in AML12 cells, the results showed that CANA significantly reduced lipid accumulation.
Hepatol Commun. 2023 Feb 9;7(3):e0045.
Rat pulmonary artery smooth muscle cells (rPASMCs)
0.5 µM to 20 µM
24 hours
To evaluate the effect of CANA on rPASMCs proliferation, results showed that CANA significantly inhibited rPASMCs proliferation under hypoxic conditions.
Acta Pharmacol Sin. 2024 Sep;45(9):1861-1878.
Canagliflozin hemihydrate/坎格列净半水合物 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Hypoxia-induced pulmonary hypertension (PH) model and Sugen 5416/hypoxia-induced severe PH model
Oral
10 mg/kg
Once daily for 21 days
To evaluate the therapeutic effect of CANA on pulmonary hypertension, results showed that CANA significantly reduced pulmonary artery pressure, right ventricular hypertrophy, and vascular remodeling.
Acta Pharmacol Sin. 2024 Sep;45(9):1861-1878.
Rats
Hypoxia-induced pulmonary hypertension (PH) model and Sugen 5416/hypoxia-induced severe PH model
Oral
5 mg/kg
Once daily for 21 days
To evaluate the therapeutic effect of CANA on pulmonary hypertension, results showed that CANA significantly reduced pulmonary artery pressure, right ventricular hypertrophy, and vascular remodeling.
Acta Pharmacol Sin. 2024 Sep;45(9):1861-1878.
Mice
Ob/ob mice and diabetic mice
Oral gavage
10 mg/kg/d
Once daily for 14 weeks
To evaluate the effect of CANA on the progression of NAFLD in ob/ob mice and diabetic mice, the results showed that CANA improved insulin sensitivity, hepatic steatosis, and inflammation.
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