Effect of Hepatic or Renal Impairment on the Pharmacokinetics of Canagliflozin, a Sodium Glucose Co-transporter 2 Inhibitor

Devineni, Damayanthi; Curtin, Christopher R.; Marbury, Thomas; Smith, William B.; Vaccaro, Nicole; Wexler, David; Vandebosch, An; Rusch, Sarah; Stieltjes, Hans; Wajs, Ewa

doi:10.1016/j.clinthera.2014.12.013

Cited by 40 publications

(38 citation statements)

References 44 publications

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“…Phlorizin is freely filtrated by the glomerulus and mainly excreted into urine, which is in line with the idea that the glomerular-filtrated phlorizin acts on SGLTs from the luminal side to increase urinary glucose excretion (Silverman, 1974). In contrast, canagliflozin exhibits high plasma protein binding (99%), and its urinary excretion is 1% or less of a single oral dosage Devineni et al, 2015;Kinoshita and Kondo, 2015). These observations raised the possibility that canagliflozin enters epithelial cells of the renal proximal tubule through the basolateral membrane to exert its inhibitory effect on SGLT2 in the apical membrane from the cytoplasmic side.…”

Section: Introductionsupporting

confidence: 78%

“…Pharmacokinetic studies have revealed that the excretion of canagliflozin in urine is ,1% of the administered dose Devineni et al, 2015;Kinoshita and Kondo, 2015). We showed that canagliflozin is incorporated into the SGLT2-expressing cells by SGLT2-mediated transport in addition to passive diffusion through the plasma membrane (Fig.…”

Section: Discussionmentioning

confidence: 82%

“…Like SGLT2, we showed that SGLT1 is preferentially inhibited by canagliflozin from the extracellular side, with a K i value of 770.5 nM. Because of the high plasma protein binding ratio (Devineni et al, 2015), the clinical dosage of canagliflozin is higher (100-300 mg) than other SGLT2 inhibitors. Therefore, it is reasonable to suppose that the luminal concentration of canagliflozin in the upper small intestine is transiently elevated after oral administration to a level considerably higher than the K i value for SGLT1, implying that canagliflozin could inhibit SGLT1 from the luminal side of the intestine.…”

Section: Discussionmentioning

confidence: 89%

“…This suggests that canagliflozin acts on SGLT2 from the luminal side because SGLT2 is localized on the apical membrane of proximal tubules . Because the plasma protein binding of canagliflozin is ∼99% (Devineni et al, 2015) and the maximal plasma concentration after oral administration of clinical doses is 2.1-6.14 mM (Kinoshita and Kondo, 2015;Sha et al, 2015), the maximal concentration of unbound canagliflozin in plasma and in the glomerular filtrate is ∼20-60 nM. SGLT2 should be exposed to this approximate canagliflozin concentration from the luminal side.…”

Section: Discussionmentioning

confidence: 99%

“…Among the selective SGLT2 inhibitors currently available for clinical use, a characteristic of canagliflozin is its modest SGLT1 inhibitory action in the intestine at clinical dosage (Grempler et al, 2012;Kuriyama et al, 2014). This is probably because of its relatively low SGLT2/SGLT1 selectivity as well as its relatively high clinical dosage, owing to its high plasma protein binding (Fujita and Inagaki, 2014;Devineni et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Interaction of the Sodium/Glucose Cotransporter (SGLT) 2 inhibitor Canagliflozin with SGLT1 and SGLT2

Ohgaki

Wei

Yamada

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Canagliflozin, a selective sodium/glucose cotransporter (SGLT) 2 inhibitor, suppresses the renal reabsorption of glucose and decreases blood glucose level in patients with type 2 diabetes. A characteristic of canagliflozin is its modest SGLT1 inhibitory action in the intestine at clinical dosage. To reveal its mechanism of action, we investigated the interaction of canagliflozin with SGLT1 and SGLT2. Inhibition kinetics and transporter-mediated uptake were examined in human SGLT1-or SGLT2-expressing cells. Whole-cell patch-clamp recording was conducted to examine the sidedness of drug action. Canagliflozin competitively inhibited SGLT1 and SGLT2, with high potency and selectivity for SGLT2. Inhibition constant (K i ) values for SGLT1 and SGLT2 were 770.5 and 4.0 nM, respectively. 14 C-canagliflozin was suggested to be transported by SGLT2; however, the transport rate was less than that of a-methyl-D-glucopyranoside. Canagliflozin inhibited a-methyl-D-glucopyranoside-induced SGLT1-and SGLT2-mediated inward currents preferentially from the extracellular side and not from the intracellular side. Based on the K i value, canagliflozin is estimated to sufficiently inhibit SGLT2 from the urinary side in renal proximal tubules. The K i value for SGLT1 suggests that canagliflozin suppresses SGLT1 in the small intestine from the luminal side, whereas it does not affect SGLT1 in the heart and skeletal muscle, considering the maximal concentration of plasma-unbound canagliflozin. Similarly, SGLT1 in the kidney would not be inhibited, thereby aiding in the prevention of hypoglycemia. After binding to SGLT2, canagliflozin may be reabsorbed by SGLT2, which leads to the low urinary excretion and prolonged drug action of canagliflozin.

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Section: Introductionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Interaction of the Sodium/Glucose Cotransporter (SGLT) 2 inhibitor Canagliflozin with SGLT1 and SGLT2

Ohgaki

Wei

Yamada

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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A validated LC‐MS/MS method for the determination of canagliflozin, a sodium–glucose co‐transporter 2 (SGLT‐2) inhibitor, in a lower volume of rat plasma: application to pharmacokinetic studies in rats

Kobuchi

Yano

Ito

et al. 2016

Biomedical Chromatography

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Canagliflozin is a novel, orally selective inhibitor of sodium-dependent glucose co-transporter-2 (SGLT2) for the treatment of patients with type 2 diabetes mellitus. In this study, a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantitative analysis of canagliflozin in a lower volume of rat plasma (0.1 mL) was established and applied to a pharmacokinetic study in rats. Following liquid-liquid extraction by tert-butyl methyl ether, chromatographic separation of canagliflozin was performed on a Quicksorb ODS (2.1 mm i.d. × 150 mm, 5 µm size) using acetonitrile-0.1% formic acid (90:10, v/v) as the mobile phase at a flow rate of 0.2 mL/min. The detection was carried out using an API 3200 triple-quadrupole mass spectrometer operating in the positive electrospray ionization mode. Selected ion monitoring transitions of m/z = 462.0 [M + NH4 ](+) → 191.0 for canagliflozin and m/z = 451.2 [M + H](+) → 71.0 for empagliflozin (internal standard) were obtained. The validation of the method was investigated, and it was found to be of sufficient specificity, accuracy and precision. Canagliflozin in rat plasma was stable under the analytical conditions used. This validated method was successfully applied to assess the pharmacokinetics of canagliflozin in rats using 0.1 mL rat plasma. Copyright © 2016 John Wiley & Sons, Ltd.

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Feasibility Study to Assess Canagliflozin Distribution and Sodium‐Glucose Co‐Transporter 2 Occupancy Using [¹⁸F]Canagliflozin in Patients with Type 2 Diabetes

Hoek

Willemsen

Visser

et al. 2023

Clin Pharma and Therapeutics

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Sodium-glucose co-transporter 2 (SGLT2) inhibitors, including canagliflozin, reduce the risk of cardiovascular and kidney outcomes in patients with and without type 2 diabetes, albeit with a large interindividual variation. The underlying mechanisms for this variation in response might be attributed to differences in SGLT2 occupancy, resulting from individual variation in plasma and tissue drug exposure and receptor availability. We performed a feasibility study for the use of [ 18 F]canagliflozin positron emission tomography (PET) imaging to determine the association between clinical canagliflozin doses and SGLT2 occupancy in patients with type 2 diabetes. We obtained two 90-minute dynamic PET scans with diagnostic intravenous [ 18 F]canagliflozin administration and a full kinetic analysis in 7 patients with type 2 diabetes. Patients received 50, 100, or 300 mg oral canagliflozin (n = 2:4:1) 2.5 hours before the second scan. Canagliflozin pharmacokinetics and urinary glucose excretion were measured. The apparent SGLT2 occupancy was derived from the difference between the apparent volume of distribution of [ 18 F]canagliflozin in the baseline and postdrug PET scans. Individual canagliflozin area under the curve from oral dosing until 24-hours (AUC P0-24h ) varied largely (range 1,715-25,747 μg/L*hour, mean 10,580 μg/L*hour) and increased dose dependently with mean values of 4,543, 6,525, and 20,012 μg/L*hour for 50, 100, and 300 mg, respectively (P = 0.046). SGLT2 occupancy ranged between 65% and 87%, but did not correlate with canagliflozin dose, plasma exposure, or urinary glucose excretion. We report the feasibility of [ 18 F]canagliflozin PET imaging to determine canagliflozin kidney disposition and SGLT2 occupancy. This suggests the potential of [ 18 F]canagliflozin as a tool to visualize and quantify clinically SGLT2 tissue binding.

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Effect of Hepatic or Renal Impairment on the Pharmacokinetics of Canagliflozin, a Sodium Glucose Co-transporter 2 Inhibitor

Cited by 40 publications

References 44 publications

Interaction of the Sodium/Glucose Cotransporter (SGLT) 2 inhibitor Canagliflozin with SGLT1 and SGLT2

Interaction of the Sodium/Glucose Cotransporter (SGLT) 2 inhibitor Canagliflozin with SGLT1 and SGLT2

A validated LC‐MS/MS method for the determination of canagliflozin, a sodium–glucose co‐transporter 2 (SGLT‐2) inhibitor, in a lower volume of rat plasma: application to pharmacokinetic studies in rats

Feasibility Study to Assess Canagliflozin Distribution and Sodium‐Glucose Co‐Transporter 2 Occupancy Using [¹⁸F]Canagliflozin in Patients with Type 2 Diabetes

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Effect of Hepatic or Renal Impairment on the Pharmacokinetics of Canagliflozin, a Sodium Glucose Co-transporter 2 Inhibitor

Cited by 40 publications

References 44 publications

Interaction of the Sodium/Glucose Cotransporter (SGLT) 2 inhibitor Canagliflozin with SGLT1 and SGLT2

Interaction of the Sodium/Glucose Cotransporter (SGLT) 2 inhibitor Canagliflozin with SGLT1 and SGLT2

A validated LC‐MS/MS method for the determination of canagliflozin, a sodium–glucose co‐transporter 2 (SGLT‐2) inhibitor, in a lower volume of rat plasma: application to pharmacokinetic studies in rats

Feasibility Study to Assess Canagliflozin Distribution and Sodium‐Glucose Co‐Transporter 2 Occupancy Using [18F]Canagliflozin in Patients with Type 2 Diabetes

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Product

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Feasibility Study to Assess Canagliflozin Distribution and Sodium‐Glucose Co‐Transporter 2 Occupancy Using [¹⁸F]Canagliflozin in Patients with Type 2 Diabetes