mSGLT2 ( IC50 = 2 nM ); rSGLT2 ( IC50 = 3.7 nM ); hSGLT2 ( IC50 = 4.4 nM )

In CHO-hSGLT2 cells, canagliflozin inhibits Na+-dependent 14C-AMG uptake with an IC50 of 4.4±1.2 nM. Rat and mouse SGLT2 have IC50 values of 2.0 nM and 3.7 nM, respectively, in CHO-mSGLT2 and CHO-rSGLT2 cells. With an IC50 of 684±159 nM and >1,000 nM, respectively, canagliflozin inhibits the absorption of 14C-AMG in CHO-hSGLT1 and mSGLT1 cells[1].

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In vitro activity: Canagliflozin is a newly discovered thiophene-ringed C-glucoside. In a concentration-dependent manner, canagliflozin inhibits 14C-AMG uptake that is dependent on Na+. In CHO-hSGLT1 and mSGLT1 cells, canagliflozin inhibits 14C-AMG uptake with IC50 values of 0.7 μM and >1 μM, respectively. Less than 50% of L6 myoblasts' facilitative (non-Na+-linked) GLUT-mediated 2H-2-DG uptake is inhibited by canagliflozin. Currents in oocytes injected with sham are unaffected by canagliflozin (10 μM) or phlorizin (3 mM) when combined with 50 μM DNJ. DMSO and Canagliflozin 10 μM inhibit DNJ-induced currents by 15.6% and 23.4%, respectively, in oocytes that have received SGLT3 injections. [1]

In DIO mice, canagliflozin (30 mg/kg) therapy for 4 weeks lowers body weight increase, respiratory exchange ratio, and blood glucose (BG) levels[1]. as canagliflozin (3 mg/kg) is administered for three weeks, rats treated with ZF experience a loss in body weight due to an increase in urine glucose excretion (UGE) without a significant change in total food consumption as compared to vehicle-treated rats[1].

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Canagliflozin exhibits strong anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice. Male SD rats given oral canagliflozin at 30 mg/kg for 24 hours experience an increase in glucose excretion of 3,696 mg per 200 g body weight. After oral administration, pharmacokinetic studies show a significantly higher exposure of canagliflozin. Male SD rats were given intravenous and oral doses of 3 and 10 mg/kg, respectively.The results show that the oral bioavailability was 85%, the po, t1/2, and AUCf0−in were 35,980 ng·h/mL, 5.2 hours, and po, respectively. Therefore, after oral dosing of canagliflozin, inhibition of SGLT2 in renal tubules is likely to continuously suppress glucose reabsorption. The broad UGE would indicate both the high potency of SGLT2 inhibition and the excellent pharmacokinetic characteristics of canagliflozin in vivo. The novel compound could be useful as an anti-diabetic agent because SGLT2 in the renal tubules reabsorbs most of the filtered glucose. In hyperglycemic high-fat diet-fed KK (HF-KK) mice, a single oral administration of canagliflozin at a dose of 3 mg/kg significantly lowered blood glucose levels without affecting food intake. After six hours, the blood glucose level is 48% lower than in the vehicle. Conversely, in normoglycemic mice, canagliflozin has a negligible effect on blood glucose levels. Canagliflozin would therefore reduce the risk of hypoglycemia while controlling hyperglycemia in the treatment of type 2 diabetes. [2]

Sodium-Dependent Glucose Uptake in CHO cells Expressing human SGLT1 and SGLT2. Parental Chinese hamster ovary-K (CHOK) cells expressing human SGLT1 and SGLT21 were used in these experiments. For the uptake assay, cells were seeded into 24-well plates, and were post-confluent on the day of assay. Cells were rinsed one time with 400 µL Assay Buffer (137 mM NaCl, 5 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 50 mM HEPES, 20 mM Tris Base, pH 7.4), and were pre-incubated with the solutions of compounds (250 µL) for 10 min at 37 °C. The transport reaction was initiated by addition of 50 µL alpha methyl-D-glucopyranoside (AMG) / 14C-AMG solution (16.7 µCi; final concentration, 0.3 mM for CHOK-SGLT1 and 0.5 mM for CHOK-SGLT2, respectively) and incubated for 120 min at 37 °C. After the incubation, the AMG uptake was halted by aspiration of the incubation mixture followed by immediate washing three times with PBS. The cells were solubilized in 0.3 N NaOH of 300 µL and the radioactivity associated with the cells was monitored by a liquid scintillation counter. Inhibitory concentration of 50% (IC50) was calculated by nonlinear least squares analysis using a four-parameter logistic model.[2]

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Two-electrode Voltage Clamp Recording of Oocytes Expressing Human SGLT3 [1]
The functional effects of canagliflozin on human SGLT3 were studied by 2-electrode voltage clamp electrophysiology using OpusXpress 6000A. Stage V–VI oocytes were injected with 50 nl of either human SGLT3 mRNA (at 1 ng/nl) or distilled water (control) and incubated at 18°C in a calcium-free solution (92 mM NaCl, 2 mM KCl, 1 mM MgCl2, 5 mM HEPES, 0.05 mg/ml gentamicin at pH 7.5) for 4–6 days before recording. The extracellular recording solution contained 92 mM NaCl, 2 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, and 5 mM HEPES at pH 7.5. Injected oocytes were impaled with 2 microelectrodes filled with 3 M KCl (resistance of ∼0.5–3 MΩ) and voltage clamped to −120 mV, at which continuous recordings were made (filtered at 5 kHz and sampled at 625 Hz). To establish the baseline in the absence of agonist, oocytes were first perfused for 85 seconds with a control buffer (92 mM NaCl, 2 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, 5 mM HEPES at pH 7.5). Next, 50 µM 1-deoxynojirimycin (DNJ) was applied for 160 seconds, followed by co-application of imino sugars 1-deoxynojirimycin (DNJ, 50 µM) with either canagliflozin (10 µM) or dimethyl sulfoxide (DMSO) (0.1%) for 160 seconds. Finally, phlorizin (3 mM) was applied in the presence of 50 µM DNJ for 160 seconds. All experiments were performed at 22°C. Currents in the presence of 50 µM DNJ were subtracted from leak currents (currents in control buffer alone) to obtain DNJ-induced currents (IDNJ). Effects of compounds were calculated as: % Inhibition = 100×(IDNJ−Icmpd)/IDNJ, where Icmpd is the DNJ-induced and leak-subtracted current in the presence of a compound or DMSO. Due to lack of effect at the highest dose tested, a dose-response relationship was not examined.

The effect of canagliflozin on the activity of the glucose transporter 1 (GLUT1) is examined in rat skeletal muscle cell line L6 cells. The culture medium used for the cells is Dulbecco's modified Eagle's medium, which contains 5.6 mM glucose and 10% fetal bovine serum. The cells are seeded in 24-well plates at a density of 3 × 10⁵ cells/well and are cultured for 24 hours at 37 °C in an atmosphere of 5% CO2. The cells are pre-incubated with the solutions of Canagliflozin (250 μL, 10 μM) for 5 minutes at room temperature after being rinsed twice with Kreb's ringer phosphate HEPES buffer (pH 7.4, 150 mM NaCl, 5 mM KCl, 1.25 mM MgSO₄, 1.25 mM CaCl2, 2.9 mM Na²HPO₄, 10 mM HEPES). 50 μL of 4.5 mM 2-DG (a GLUTs substrate)/3H-2-DG (0.625 μCi) is added to start the transport reaction, which is then incubated for 15 minutes at room temperature. Aspiration of the incubation mixture stops the uptake of 2-DG. The cells are instantly cleaned three times in ice-cold PBS. Radioactivity is measured using liquid scintillation after samples are extracted using 0.3 N NaOH.

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Cell-based Assays [1]
Sodium-dependent Glucose Uptake in Chinese Hamster Ovary (CHO) Cells Expressing SGLT1 and SGLT2 Co-transporters Parental CHO-K (CHOK) cells (commonly used mammalian cells for gene overexpression studies) expressing human or mouse SGLT1 and SGLT2 were utilized in this study. Cells were seeded into 96-well plates. Cells were then washed one time with 0.15 ml assay buffer (137 mM NaCl, 5 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 50 mM HEPES, pH 7.4) at 37°C. After the assay buffer was removed, 50 µl of fresh assay buffer with 5 µl of canagliflozin (0.3–300 nM) was added, followed by 10 minutes of incubation. Then, 5 µl of 6 mM alpha-methyl-d-glucopyranoside (AMG, a selective SGLT1/2 substrate)/14C-AMG (0.07 µCi) was added to the cells and incubated at 37°C for 2 hours. Next, the cells were washed 3 times with 0.15 ml ice-cold phosphate-buffered saline (PBS). After the final wash was aspirated, 50 µl of microscint 20 was added. The plate was counted by TopCount.

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The 2-deoxy-glucose (2-DG) Uptake in L6 Myoblast Cells [1]
Cells from the rat skeletal muscle cell line, L6, was used to test the effect of canagliflozin on glucose transporter 1 (GLUT1) activity. Cells were maintained in Dulbecco's modified Eagle's medium containing 5.6 mM glucose supplemented with 10% fetal bovine serum, were seeded in 24-well plates at a density of 3.0×105 cells/well and cultured for 24 hours in an atmosphere of 5% CO2 at 37°C. Cells were rinsed twice with Kreb's ringer phosphate HEPES buffer (pH 7.4, 150 mM NaCl, 5 mM KCl, 1.25 mM MgSO4, 1.25 mM CaCl2, 2.9 mM Na2HPO4, 10 mM HEPES) and were pre-incubated with the solutions of canagliflozin (250 µl, 10 uM) for 5 minutes at room temperature. The transport reaction was initiated by adding 50 µl of 4.5 mM 2-DG (a substrate for GLUTs)/3H-2-DG (0.625 µCi) followed by incubation for 15 minutes at room temperature. The 2-DG uptake was halted by aspiration of the incubation mixture. Cells were immediately washed 3 times with ice-cold PBS. Samples were extracted with 0.3 N NaOH, and radioactivity was determined by liquid scintillation.

Animal/Disease Models: Diet-induced obese, insulin resistantmice (DIO) Mice[1]
Doses: 30 mg/kg
Route of Administration: po (oral gavage); daily; 4 weeks
Experimental Results: decreased BG levels, respiratory exchange ratio, and body weight gain.

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Animal/Disease Models: Male Zucker fatty (ZF) obese, insulin resistant rats[1]
Doses: 3 mg /kg
Route of Administration: po (oral gavage); daily; 3 weeks
Experimental Results: UGE was increased with no significant change in total food intake compared with that in vehicle-treated rats, leading to a decrease in body weight.

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Animals and canagliflozin Administration [1]
Four rodent models were used in these experiments: (1) male C57BL/6J mice fed with a high-fat diet (D-12492 with 60 kcal% fat) (diet-induced obese, insulin resistantmice [DIO]); (2) male C57BL/ksj-db/db hyperglycemic mice; (3) male Zucker fatty (ZF) obese, insulin resistant rats; and (4) male ZDF obese, hyperglycemic rats. Canagliflozin was formulated in 0.5% hydroxypropyl methylcellulose and administrated via oral gavage at 10 ml/kg.

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Reduction of Hyperglycemia in Diabetic Rodent Models [1]
To examine the effect of canagliflozin on hyperglycemia, single doses of canagliflozin (0.1, 1, and 10 mg/kg) were administered to overnight-fasted db/db mice. BG levels were monitored at 0, 0.5, 1, 3, 6, and 24 hours after dosing. Canagliflozin was also administered to ZDF rats at varying doses (3–30 mg/kg) for 4 weeks to evaluate its effect on BG control and pancreatic beta-cell function. BG levels were monitored weekly, and HbA1c, plasma glucose, and insulin levels were determined at the end of the 4-week treatment. An oral glucose tolerance test (OGTT) (2 mg/kg of body weight, given by gavage) was conducted in ZDF rats after 4 weeks of treatment. Blood was sampled at 0, 30, 60, and 120 minutes after glucose challenge from the tail vein for measurement of BG levels using a glucometer and plasma insulin using ELISA method.

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Body Weight Control Studies in Obese Mice and Rats [1]
The effects of canagliflozin on body weight gain were evaluated in DIO mice and ZF rats. DIO mice received a 4-week treatment of canagliflozin at 30 mg/kg. Body weight, food intake, and BG levels were monitored weekly. UGE and indirect calorimetry were conducted in the fourth week of treatment during the compound treatment. In another study, ZF rats were treated with canagliflozin at 3 mg/kg for 3 weeks. Body weight, food intake, and BG were measured weekly during the 19-day treatment period. UGE, body fat, and indirect calorimetric studies were conducted at the end of this study.

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Urinary Glucose Excretion (UGE) Study. [1]
Male Sprague-Dawley (SD) rats aged 4-5 weeks were used for experiments at 6 weeks of age after acclimation period. The animals were divided into experimental groups matched for body weight (n = 2-3). The compounds were prepared in vehicles as suspension or solution. UGE studies were performed after two-day acclimation period in metabolic cages. The compounds (canagliflozin) or vehicle were orally administered at a dose of 30 mg/kg in 0.2% CMC/0.2% Tween 80. Urine samples were collected for 24 hours using metabolic cages to measure urinary glucose excretion. Urine glucose contents were determined by an enzymatic assay kit (UGLU-L). All animals were allowed free access to a standard pellet diet (CRF1) and tap water.

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Single Oral Dosing Study. [1]
Male KK/Ta Jcl mice aged 9 weeks were kept on a standard diet (CRF-1; 5.7% (w/w) fat, 3.59 kcal/g), 20-week-old mice were fed with a high-fat diet (60 kcal%) for 4 weeks. The experiment was carried out at the age of 24 weeks. Male C57BL/6N mice aged 11 weeks were also used in this study. The animals were divided into experimental groups matched for body weight and blood glucose levels, which were measured in the fed state on the day of the experiment. The compounds (canagliflozin; 3 mg/kg) or vehicle (0.2% CMC/0.2% Tween 80) were orally administered at a volume of 10 mL/kg. The blood samples were collected from the tail vein before and at 1, 2, 4, 6 and 24 hr after the administration. The blood glucose level was determined using commercially available kits based on the glucose oxidase method. Data are expressed as means ± SEM. Area under the curve for blood glucose levels (AUCglucose 0-6 hr) was calculated by the trapezoidal rule.

Absorption, Distribution and Excretion
**Bioavailability and steady-state** The absolute oral bioavailability of canagliflozin, on average, is approximately 65%. Steady-state concentrations are achieved after 4 to 5 days of daily dose administration between the range of 100mg to 300mg. **Effect of food on absorption** Co-administration of a high-fat meal with canagliflozin exerted no appreciable effect on the pharmacokinetic parameters of canagliflozin. This drug may be administered without regard to food. Despite this, because of the potential of canagliflozin to decrease postprandial plasma glucose excretion due to prolonged intestinal glucose absorption, it is advisable to take this drug before the first meal of the day.
After a single oral radiolabeled dose canagliflozin dose to healthy subjects, the following ratios of canagliflozin or metabolites were measured in the feces and urine: **Feces** 41.5% as the unchanged radiolabeled drug 7.0% as a hydroxylated metabolite 3.2% as an O-glucuronide metabolite **Urine** About 33% of the ingested radiolabled dose was measured in the urine, generally in the form of O-glucuronide metabolites. Less than 1% of the dose was found excreted as unchanged drug in urine.
This drug is extensively distributed throughout the body. On average, the volume of distribution of canagliflozin at steady state following a single intravenous dose in healthy patients was measured to be 83.5 L.
In healthy subjects, canagliflozin clearance was approximately 192 mL/min after intravenous (IV) administration. The renal clearance of 100 mg and 300 mg doses of canagliflozin was measured to be in the range of 1.30 - 1.55 mL/min.
/MILK/ Canagliflozin is distributed into milk in rats; it is not known whether the drug is distributed into human milk.
Canagliflozin is an oral antihyperglycemic agent used for the treatment of type 2 diabetes mellitus. It blocks the reabsorption of glucose in the proximal renal tubule by inhibiting the sodium-glucose cotransporter 2. This article describes the in vivo biotransformation and disposition of canagliflozin after a single oral dose of [(14)C]canagliflozin to intact and bile duct-cannulated (BDC) mice and rats and to intact dogs and humans. Fecal excretion was the primary route of elimination of drug-derived radioactivity in both animals and humans. In BDC mice and rats, most radioactivity was excreted in bile. The extent of radioactivity excreted in urine as a percentage of the administered [(14)C]canagliflozin dose was 1.2%-7.6% in animals and approximately 33% in humans. The primary pathways contributing to the metabolic clearance of canagliflozin were oxidation in animals and direct glucuronidation of canagliflozin in humans. Unchanged canagliflozin was the major component in systemic circulation in all species. In human plasma, two pharmacologically inactive O-glucuronide conjugates of canagliflozin, M5 and M7, represented 19% and 14% of total drug-related exposure and were considered major human metabolites. Plasma concentrations of M5 and M7 in mice and rats from repeated dose safety studies were lower than those in humans given canagliflozin at the maximum recommended dose of 300 mg. However, biliary metabolite profiling in rodents indicated that mouse and rat livers had significant exposure to M5 and M7. Pharmacologic inactivity and high water solubility of M5 and M7 support glucuronidation of canagliflozin as a safe detoxification pathway.
The mean absolute oral bioavailability of canagliflozin is approximately 65%. Co-administration of a high-fat meal with canagliflozin had no effect on the pharmacokinetics of canagliflozin; therefore, INVOKANA may be taken with or without food. However, based on the potential to reduce postprandial plasma glucose excursions due to delayed intestinal glucose absorption, it is recommended that INVOKANA be taken before the first meal of the day. The mean steady-state volume of distribution of canagliflozin following a single intravenous infusion in healthy subjects was 119 L, suggesting extensive tissue distribution. Canagliflozin is extensively bound to proteins in plasma (99%), mainly to albumin. Protein binding is independent of canagliflozin plasma concentrations. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment. Following administration of a single oral [14C] canagliflozin dose to healthy subjects, 41.5%, 7.0%, and 3.2% of the administered radioactive dose was recovered in feces as canagliflozin, a hydroxylated metabolite, and an O-glucuronide metabolite, respectively. Enterohepatic circulation of canagliflozin was negligible. Approximately 33% of the administered radioactive dose was excreted in urine, mainly as O-glucuronide metabolites (30.5%). Less than 1% of the dose was excreted as unchanged canagliflozin in urine. Renal clearance of canagliflozin 100 mg and 300 mg doses ranged from 1.30 to 1.55 mL/min. Mean systemic clearance of canagliflozin was approximately 192 mL/min in healthy subjects following intravenous administration.

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Metabolism / Metabolites
Canagliflozin is primarily metabolized by O-glucuronidation. It is mainly glucuronidated by UGT1A9 and UGT2B4 enzymes to two inactive O-glucuronide metabolites. The oxidative metabolism of canagliflozin by hepatic cytochrome enzyme CYP3A4 is negligible (about 7%) in humans.
O-glucuronidation is the major metabolic elimination pathway for canagliflozin, which is mainly glucuronidated by UGT1A9 and UGT2B4 to two inactive O-glucuronide metabolites. CYP3A4-mediated (oxidative) metabolism of canagliflozin is minimal (approximately 7%) in humans.

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Biological Half-Life
In a clinical study, the terminal half-life of canagliflozin was 10.6 hours for the 100mg dose and 13.1 hours for the 300 mg dose.

Toxicity Summary
IDENTIFICATION AND USE: Canagliflozin, an oral inhibitor of sodium/glucose cotransporter 2 (SGLT2) in the kidneys, leads to glucosuria and provides a unique mechanism to lower blood glucose levels in diabetes. HUMAN EXPOSURE AND TOXICITY: Canagliflozin is used for the treatment of type 2 diabetes. This agent lowers blood glucose mainly by increasing urinary glucose excretion through inhibition of sodium glucose co-transporter 2 (SGLT2) in the kidneys. Data derived from randomized clinical trials lasting up to 52 weeks suggest that canagliflozin is generally well tolerated. The most common adverse effects are genital mycotic infections occurring in 11-15% of women exposed to canagliflozin versus 2-4% of those randomized to glimepiride or sitagliptin. In men, corresponding proportions are 8-9% versus 0.5-1%. Urinary tract infections (UTI) are slightly increased (5-7%) with the use of canagliflozin compared with placebo (4%). The risk of hypoglycemia associated with canagliflozin is marginally higher than placebo, but markedly increases when the drug is used in conjunction of insulin or sulfonylureas (SU), in patients with chronic kidney disease (CKD), and in the elderly. Worsening renal function and hyperkalemia may occur in patients using canagliflozin, particularly in patients with underlying CKD. Mild weight loss (mean 2-4 kg) and lowering of blood pressure represent 2 advantages of canagliflozin owing to its osmotic diuretic effect. However, the latter action may lead to postural hypotension and dizziness in susceptible subjects. Another concerning adverse effect of canagliflozin is an average 8% increase in plasma levels of low-density lipoprotein cholesterol (LDL-C) compared with placebo. Adverse effects such as increased urinary frequency, genital mycotic infections, and urinary tract infections may discourage the use of the drug in the elderly patient. ANIMAL STUDIES: The carcinogenicity potential of canagliflozin was evaluated in a 2-year rat study (10, 30, and 100 mg/kg). Rats showed an increase in pheochromocytomas, renal tubular tumors, and testicular Leydig cell tumors. Leydig cell tumors were associated with increased luteinizing hormone levels and pheochromocytomas were most likely related to glucose malabsorption and altered calcium homeostasis. Renal tubular tumors may also have been linked to glucose malabsorption. Canagliflozin did not increase the incidence of tumors in mice dosed at 10, 30, or 100 mg/kg. In a juvenile toxicity study in which canagliflozin was dosed directly to young rats from postnatal day (PND) 21 until PND 90 at doses of 4, 20, 65, or 100 mg/kg, increased kidney weights and a dose-related increase in the incidence and severity of renal pelvic and renal tubular dilatation were reported at all dose levels. Exposure at the lowest dose tested was greater than or equal to 0.5 times the maximum clinical dose of 300 mg. The renal pelvic dilatations observed in juvenile animals did not fully reverse within the 1-month recovery period. Similar effects on the developing kidney were not seen when canagliflozin was administered to pregnant rats or rabbits during the period of organogenesis or during a study in which maternal rats were dosed from gestation day (GD) 6 through PND 21 and pups were indirectly exposed in utero and throughout lactation. Canagliflozin had no effects on the ability of rats to mate and sire or maintain a litter up to the high dose of 100 mg/kg (approximately 14 times and 18 times the 300 mg clinical dose in males and females, respectively), although there were minor alterations in a number of reproductive parameters (decreased sperm velocity, increased number of abnormal sperm, slightly fewer corpora lutea, fewer implantation sites, and smaller litter sizes) at the highest dosage administered. Canagliflozin was not mutagenic with or without metabolic activation in the Ames assay. Canagliflozin was mutagenic in the in vitro mouse lymphoma assay with but not without metabolic activation. Canagliflozin was not mutagenic or clastogenic in an in vivo oral micronucleus assay in rats and an in vivo oral Comet assay in rats.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of canagliflozin during breastfeeding. Canagliflozin is an uncharged molecule that is 99% protein bound in plasma, so it is unlikely to pass into breastmilk in clinically important amounts. The manufacturer does not recommend canagliflozin during breastfeeding because of a theoretical risk to the infant's developing kidney. An alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Canagliflozin is mainly bound to albumin. The plasma protein binding of this drug is 99%.

[1]. Effect of canagliflozin on renal threshold for glucose, glycemia, and body weight in normal and diabetic animal models. PLoS One. 2012;7(2):e30555.

[2]. Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J Med Chem. 2010 Sep 9;53(17):6355-60.

Canagliflozin hydrate is a hydrate that is the hemihydrate form of canagliflozin. Used for treatment of type II diabetes via inhibition of sodium-glucose transport protein subtype 2. It has a role as a hypoglycemic agent and a sodium-glucose transport protein subtype 2 inhibitor. It contains a canagliflozin.
Canagliflozin is a C-glucoside with a thiophene ring that is an orally available inhibitor of sodium-glucose transporter 2 (SGLT2) with antihyperglycemic activity. Canagliflozin is also able to reduce body weight and has a low risk for hypoglycemia.
A glucoside-derived SODIUM-GLUCOSE TRANSPORTER 2 inhibitor that stimulates urinary excretion of glucose by suppressing renal glucose reabsorption. It is used to manage BLOOD GLUCOSE levels in patients with TYPE 2 DIABETES.

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Drug Indication
Invokana is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise: as monotherapy when metformin is considered inappropriate due to intolerance or contraindicationsin addition to other medicinal products for the treatment of diabetes. For study results with respect to combination of therapies, effects on glycaemic control, cardiovascular and renal events, and the populations studied, see sections 4. 4, 4. 5 and 5. 1.

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Canagliflozin is a C-glycosyl compound that is used (in its hemihydrate form) for treatment of type II diabetes via inhibition of sodium-glucose transport protein subtype 2. It has a role as a hypoglycemic agent and a sodium-glucose transport protein subtype 2 inhibitor. It is a C-glycosyl compound, a member of thiophenes and an organofluorine compound.
Canagliflozin, also known as Invokana, is a sodium-glucose cotransporter 2 (SGLT2) inhibitor used in the management of type 2 diabetes mellitus along with lifestyle changes including diet and exercise. It was initially approved by the FDA in 2013 for the management of diabetes and later approved in 2018 for a second indication of reducing the risk of cardiovascular events in patients diagnosed with type 2 diabetes mellitus,. Canagliflozin is the first oral antidiabetic drug approved for the prevention of cardiovascular events in patients with type 2 diabetes. Cardiovascular disease is the most common cause of death in these patients.
Canagliflozin anhydrous is a Sodium-Glucose Cotransporter 2 Inhibitor. The mechanism of action of canagliflozin anhydrous is as a Sodium-Glucose Transporter 2 Inhibitor, and P-Glycoprotein Inhibitor.
Canagliflozin is a C-glucoside with a thiophene ring that is an orally available inhibitor of sodium-glucose transporter 2 (SGLT2) with antihyperglycemic activity. Canagliflozin is also able to reduce body weight and has a low risk for hypoglycemia.
Canagliflozin Anhydrous is the anhydrous form of canagliflozin, a C-glucoside with a thiophene ring that is an orally available inhibitor of sodium-glucose transporter 2 (SGLT2) with antihyperglycemic activity. Canagliflozin is also able to reduce body weight and has a low risk for hypoglycemia.
A glucoside-derived SODIUM-GLUCOSE TRANSPORTER 2 inhibitor that stimulates urinary excretion of glucose by suppressing renal glucose reabsorption. It is used to manage BLOOD GLUCOSE levels in patients with TYPE 2 DIABETES.

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Drug Indication
This drug is used in conjunction with diet and exercise to increase glycemic control in adults diagnosed with type 2 diabetes mellitus. Another indication for canagliflozin is the prevention of major cardiovascular events (myocardial infarction, stroke, or death due to a cardiovascular cause) in patients with type 2 diabetes, as well as hospitalization for heart failure in patients with type 2 diabetes[L5897,. In addition to the above, canagliflozin can be used to lower the risk of end-stage kidney disease and major increases in serum creatinine and cardiovascular death for patients with a combination of type 2 diabetes mellitus, diabetic nephropathy, and albuminuria. It is important to note that this drug is **not** indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
FDA Label
Invokana is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise: as monotherapy when metformin is considered inappropriate due to intolerance or contraindicationsin addition to other medicinal products for the treatment of diabetes. For study results with respect to combination of therapies, effects on glycaemic control, cardiovascular and renal events, and the populations studied, see sections 4. 4, 4. 5 and 5. 1.
Treatment of type II diabetes mellitus

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Mechanism of Action
The sodium-glucose co-transporter2 (SGLT2), is found in the proximal tubules of the kidney, and reabsorbs filtered glucose from the renal tubular lumen. Canagliflozin inhibits the SGLT2 co-transporter. This inhibition leads to lower reabsorption of filtered glucose into the body and decreases the renal threshold for glucose (RTG), leading to increased glucose excretion in the urine.
Sodium-glucose co-transporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion (UGE).

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Background: Canagliflozin is a sodium glucose co-transporter (SGLT) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus (T2DM). Methods: (14)C-alpha-methylglucoside uptake in Chinese hamster ovary-K cells expressing human, rat, or mouse SGLT2 or SGLT1; (3)H-2-deoxy-d-glucose uptake in L6 myoblasts; and 2-electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed. Graded glucose infusions were performed to determine rate of urinary glucose excretion (UGE) at different blood glucose (BG) concentrations and the renal threshold for glucose excretion (RT(G)) in vehicle or canagliflozin-treated Zucker diabetic fatty (ZDF) rats. This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity. Results: Treatment with canagliflozin 1 mg/kg lowered RT(G) from 415±12 mg/dl to 94±10 mg/dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT(G). Canagliflozin dose-dependently decreased BG concentrations in db/db mice treated acutely. In ZDF rats treated for 4 weeks, canagliflozin decreased glycated hemoglobin (HbA1c) and improved measures of insulin secretion. In obese animal models, canagliflozin increased UGE and decreased BG, body weight gain, epididymal fat, liver weight, and the respiratory exchange ratio. Conclusions: Canagliflozin lowered RT(G) and increased UGE, improved glycemic control and beta-cell function in rodent models of T2DM, and reduced body weight gain in rodent models of obesity.[1]

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We discovered that C-glucosides 4 bearing a heteroaromatic ring formed metabolically more stable inhibitors for sodium-dependent glucose cotransporter 2 (SGLT2) than the O-glucoside, 2 (T-1095). A novel thiophene derivative 4b-3 (canagliflozin) was a highly potent and selective SGLT2 inhibitor and showed pronounced anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice.[2]

C48H52F2O11S2

907.05

906.291

C, 63.56; H, 5.78; F, 4.19; O, 19.40; S, 7.07

928672-86-0

Canagliflozin;842133-18-0

24997615

Off-white to yellow solid powder

5.872

9

15

10

63

574

10

CC1=C(C=C(C=C1)[C@H]2[C@@H]([C@H]([C@@H]([C@H](O2)CO)O)O)O)CC3=CC=C(S3)C4=CC=C(C=C4)F.CC1=C(C=C(C=C1)[C@H]2[C@@H]([C@H]([C@@H]([C@H](O2)CO)O)O)O)CC3=CC=C(S3)C4=CC=C(C=C4)F.O

VHOFTEAWFCUTOS-TUGBYPPCSA-N

InChI=1S/2C24H25FO5S.H2O/c2*1-13-2-3-15(24-23(29)22(28)21(27)19(12-26)30-24)10-16(13)11-18-8-9-20(31-18)14-4-6-17(25)7-5-14;/h2*2-10,19,21-24,26-29H,11-12H2,1H3;1H2/t2*19-,21-,22+,23-,24+;/m11./s1

(2S,3R,4R,5S,6R)-2-[3-[[5-(4-fluorophenyl)thiophen-2-yl]methyl]-4-methylphenyl]-6-(hydroxymethyl)oxane-3,4,5-triol;hydrate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.51 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.51 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.51 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 0.5% CMC+0.25% Tween 80 :18 mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)