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

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]

Canagliflozin is a highly potent and selective SGLT2 inhibitor for hSGLT2 with IC50 of 2.2 nM, and exhibits 413-fold selectivity over hSGLT1.
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.

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.

Dissolved in 0.2% CMC/0.2% Tween 80; 10 mg/kg; oral administration.

KK (HF-KK) mice

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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Interactions
Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) reduce hyperglycaemia by decreasing renal glucose threshold and thereby increasing urinary glucose excretion. They are proposed as a novel approach for the management of type 2 diabetes mellitus. They have proven their efficacy in reducing glycated haemoglobin, without inducing hypoglycaemia, as monotherapy or in combination with various other glucose-lowering agents, with the add-on value of promoting some weight loss and lowering arterial blood pressure. As they may be used concomitantly with many other drugs, we review the potential drug-drug interactions (DDIs) regarding the three leaders in the class (dapagliglozin, canagliflozin and empagliflozin). Most of the available studies were performed in healthy volunteers and have assessed the pharmacokinetic interferences with a single administration of the SGLT2 inhibitor. The exposure [assessed by peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC)] to each SGLT2 inhibitor tested was not significantly influenced by the concomitant administration of other glucose-lowering agents or cardiovascular agents commonly used in patients with type 2 diabetes. Reciprocally, these medications did not influence the pharmacokinetic parameters of dapagliflozin, canagliflozin or empagliflozin. Some modest changes were not considered as clinically relevant. However, drugs that could specifically interfere with the metabolic pathways of SGLT2 inhibitors [rifampicin, inhibitors or inducers of uridine diphosphate-glucuronosyltransferase (UGT)] may result in significant changes in the exposure of SGLT2 inhibitors, as shown for dapagliflozin and canagliflozin. Potential DDIs in patients with type 2 diabetes receiving chronic treatment with an SGLT2 inhibitor deserve further attention, especially in individuals treated with several medications or in more fragile patients with hepatic and/or renal impairment.
Digoxin: There was an increase in the AUC and mean peak drug concentration (C max) of digoxin (20% and 36%, respectively) when co-administered with INVOKANA 300 mg. Patients taking INVOKANA with concomitant digoxin should be monitored appropriately.
Concomitant use of canagliflozin with drugs that interfere with the renin-angiotensin-aldosterone system, including angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists, may increase the incidence of symptomatic hypotension. Prior to initiating canagliflozin in such patients, intravascular volume should be assessed and corrected; patients should be monitored for signs and symptoms of hypotension after initiating therapy. These drugs also may cause hyperkalemia in patients with moderate renal impairment. Serum potassium concentrations should be monitored periodically following initiation of canagliflozin in patients predisposed to hyperkalemia due to drug therapy.
UGT Enzyme Inducers: Rifampin: Co-administration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy. If an inducer of these UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) must be co-administered with INVOKANA (canagliflozin), consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA 100 mg once daily, have an eGFR greater than 60 mL/min/1.73 m squared, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to less than 60 mL/min/1.73 m squared receiving concurrent therapy with a UGT inducer and require additional glycemic control
For more Interactions (Complete) data for Canagliflozin (6 total), please visit the HSDB record page.

[1]. PLoS One. 2012;7(2):e30555.

[2]. J Med Chem. 2010 Sep 9;53(17):6355-60.

Therapeutic Uses
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Canagliflozin is included in the database.
Invokana (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. /Included in US product label/
EXPL THER The proximal tubule's sodium-glucose linked transporter-2 (SGLT2) accounts for the vast majority of glucose reabsorption by the kidney. Its selective inhibition, accordingly, leads to substantial glycosuria, lowering blood glucose, and facilitating weight loss in individuals with diabetes. During the past year, two SGLT2 inhibitors, canagliflozin and dapagliflozin, have been approved for the treatment of type 2 diabetes. Beyond their anti-hyperglycemic properties, however, this new class of drugs has several other attributes that provide a theoretical basis for kidney protection. Like agents that block the renin-angiotensin system, SGLT2 inhibitors also reduce single-nephron glomerular filtration rate (SNGFR) in the chronically diseased kidney, though by quite different mechanisms. Additional potentially beneficial effects of SGLT2 inhibition include modest reductions in blood pressure and plasma uric acid. Finally, cell culture studies indicate that glucose uptake from the tubular lumen, as well as from the basolateral compartment, can contribute to proximal tubular production of extracellular matrix proteins. Whether such attributes will translate into reducing the progression of chronic kidney disease will require the undertaking of long-term, dedicated studies.
EXPL THER Management of hypertension in diabetes is critical for reduction of cardiovascular mortality and morbidity. While blood pressure (BP) control has improved over the past two decades, the control rate is still well below 50% in the general population of patients with type 2 diabetes mellitus (T2DM). A new class of oral glucose-lowering agents has recently been approved; the sodium-glucose co-transporter 2 (SGLT2) inhibitors, which act by eliminating large amounts of glucose in the urine. Two agents, dapagliflozin and canagliflozin, are currently approved in the United States and Europe, and empagliflozin and ipragliflozin have reported Phase 3 trials. In addition to glucose lowering, SGLT2 inhibitors are associated with weight loss and act as osmotic diuretics, resulting in a lowering of BP. While not approved for BP-lowering, they may potentially aid BP goal achievement in people within 7-10 mm Hg of goal.

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Drug Warnings
Hypersensitivity reactions (e.g., generalized urticaria), some serious, have been reported with canagliflozin treatment. These reactions generally occurred within hours to days of canagliflozin initiation. If a hypersensitivity reaction occurs, the drug should be discontinued, appropriate treatment instituted, and the patient monitored until signs and symptoms resolve.
Dose-dependent increases in low-density lipoprotein (LDL)-cholesterol can occur during canagliflozin therapy. Serum LDL-cholesterol concentrations should be monitored during treatment with canagliflozin and such lipid elevations treated according to the standard of care.
When canagliflozin is added to therapy with an insulin secretagogue (e.g., a sulfonylurea) or insulin, the incidence of hypoglycemia is increased compared with sulfonylurea or insulin monotherapy. Therefore, patients receiving canagliflozin may require a reduced dosage of the concomitant insulin secretagogue or insulin to reduce the risk of hypoglycemia.
Canagliflozin may increase the risk of genital mycotic infections in males (e.g., balanoposthitis, candidal balanitis) and females (e.g., vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis). In clinical trials, patients with a history of genital mycotic infections and uncircumcised males were more likely to develop such infections. Patients should be monitored for genital mycotic infections and appropriate treatment should be instituted if these infections occur.
For more Drug Warnings (Complete) data for Canagliflozin (14 total), please visit the HSDB record page.

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Pharmacodynamics
This drug increases urinary glucose excretion and decreases the renal threshold for glucose (RTG) in a dose-dependent manner. The renal threshold is defined as the lowest level of blood glucose associated with the appearance of detectable glucose in the urine. The end result of canagliflozin administration is increased urinary excretion of glucose and less renal absorption of glucose, decreasing glucose concentration in the blood and improving glycemic control. **A note on type 2 diabetes and cardiovascular disease** The risk of cardiovascular events in diabetes type 2 is increased due to the damaging effects of diabetes on blood vessels and nerves in the cardiovascular system. In particular, there is a tendency for hyperglycemia to create pro-atherogenic (plaque forming) lesions in blood vessels, leading to various fatal and non-fatal events including stroke and myocardial infarction. Long-term glycemic control has been proven to be effective in the prevention of cardiovascular events such as myocardial infarction and stroke in patients with type 2 diabetes.

C24H25FO5S

444.52

444.14

C, 64.85; H, 5.67; F, 4.27; O, 18.00; S, 7.21

842133-18-0

Canagliflozin hemihydrate; 928672-86-0; Canagliflozin-d4; 1997338-61-0; Canagliflozin-d6

24812758

White solid powder

1.4±0.1 g/cm3

642.9±55.0 °C at 760 mmHg

68-72

342.6±31.5 °C

0.0±2.0 mmHg at 25°C

1.639

5.34

4

7

5

31

574

5

O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1C=CC(C)=C(CC2=CC=C(C3C=CC(F)=CC=3)S2)C=1

XTNGUQKDFGDXSJ-ZXGKGEBGSA-N

InChI=1S/C24H25FO5S/c1-13-2-3-15(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/h2-10,19,21-24,26-29H,11-12H2,1H3/t19-,21-,22+,23-,24+/m1/s1

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

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 (5.62 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
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 (5.62 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
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: ≥ 2.08 mg/mL (4.68 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 20.8 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 4: ≥ 2.08 mg/mL (4.68 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 20.8 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 5: ≥ 2.08 mg/mL (4.68 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 6: ≥ 0.5 mg/mL (1.12 mM) (saturation unknown) in 1% DMSO 99% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
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 7: 0.5% CMC+0.25% Tween 80 : 18 mg/mL

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