Pharmacokinetics and pharmacodynamics of dapagliflozin, a novel selective inhibitor of sodium-glucose co-transporter type 2, in Japanese subjects without and with type 2 diabetes mellitus

Kasichayanula, Sreeneeranj; Chang, Ming; Hasegawa, Mayumi; Liu, X.; Yamahira, Naomi; LaCreta, Frank; Imai, Yasuhiko; Boulton, David W.

doi:10.1111/j.1463-1326.2011.01359.x

Cited by 101 publications

(112 citation statements)

References 13 publications

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“…The mouse data are similar to both our F-Dapa (not shown) and the [ 14 C] dapagliflozin results in human subjects. 17 After displacing F-Dapa from the kidney, we observed a transient increase in the concentration of F-Dapa in plasma, especially in the renal vein ( Figure 5B). This along with the lack of F-Dapa binding in the renal medulla ( Figure 6) indicate that F-Dapa is reabsorbed by nephrons back into blood.…”

Section: F-dapa Excretion and Metabolismmentioning

confidence: 90%

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Dapagliflozin Binds Specifically to Sodium-Glucose Cotransporter 2 in the Proximal Renal Tubule

Ghezzi¹,

Hirayama³

et al. 2016

JASN

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Kidneys contribute to glucose homeostasis by reabsorbing filtered glucose in the proximal tubules via sodium-glucose cotransporters (SGLTs). Reabsorption is primarily handled by SGLT2, and SGLT2-specific inhibitors, including dapagliflozin, canagliflozin, and empagliflozin, increase glucose excretion and lower blood glucose levels. To resolve unanswered questions about these inhibitors, we developed a novel approach to map the distribution of functional SGLT2 proteins in rodents using positron emission tomography with 4-[ 18 F]fluoro-dapagliflozin (F-Dapa). We detected prominent binding of intravenously injected F-Dapa in the kidney cortexes of rats and wild-type and Sglt1-knockout mice but not Sglt2-knockout mice, and injection of SGLT2 inhibitors prevented this binding. Furthermore, imaging revealed only low levels of F-Dapa in the urinary bladder, even after displacement of kidney binding with dapagliflozin. Microscopic ex vitro autoradiography of kidney showed F-Dapa binding to the apical surface of early proximal tubules. Notably, in vivo imaging did not show measureable specific binding of F-Dapa in heart, muscle, salivary glands, liver, or brain. We propose that F-Dapa is freely filtered by the kidney, binds to SGLT2 in the apical membranes of the early proximal tubule, and is subsequently reabsorbed into blood. The high density of functional SGLT2 transporters detected in the apical membrane of the proximal tubule but not detected in other organs likely accounts for the high kidney specificity of SGLT2 inhibitors. Overall, these data are consistent with data from clinical studies on SGLT2 inhibitors and provide a rationale for the mode of action of these drugs.

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Section: F-dapa Excretion and Metabolismmentioning

confidence: 90%

“…The identity of the 18 F metabolites in plasma and urine has not yet been determined, but the major band in mouse plasma and urine may be F-dapagliflozin-3-O-glucuronide, the major metabolite found in human plasma and urine. 17 Finally, 97% of the activity extracted from rat kidney was F-Dapa.…”

Section: Metabolites Of F-dapamentioning

confidence: 99%

Dapagliflozin Binds Specifically to Sodium-Glucose Cotransporter 2 in the Proximal Renal Tubule

Ghezzi¹,

Hirayama³

et al. 2016

JASN

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“…Several SGLT2-selective inhibitors are in various stages of clinical trials (Aires and Calado, 2010;Nair and Wilding, 2010;Sha et al, 2011); proof-of-concept has been reported with dapagliflozin (Meng et al, 2008) in phase 2b studies in patients with type 2 diabetes Kasichayanula et al, 2011). Results from a 24-week phase 3 clinical study with dapagliflozin have also demonstrated significant mean reductions in the primary endpoint, glycosylated hemoglobin levels and in the secondary endpoint, fasting plasma glucose, when added to metformin in people with T2DM inadequately controlled with metformin alone (Bailey et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Preclinical Species and Human Disposition of PF-04971729, a Selective Inhibitor of the Sodium-Dependent Glucose Cotransporter 2 and Clinical Candidate for the Treatment of Type 2 Diabetes Mellitus

Kalgutkar¹,

Tugnait²,

Zhu³

et al. 2011

Drug Metab Dispos

128

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C]metformin by PF-04971729 also were very weak (IC 50 ‫؍‬ ϳ900 M). Single-species allometric scaling of rat pharmacokinetics of PF-04971729 was used to predict human clearance, distribution volume, and oral bioavailability. Human pharmacokinetic predictions were consistent with the potential for a low daily dose. First-in-human studies after oral administration indicated that the human pharmacokinetics/dose predictions for PF-04971729 were in the range that is likely to yield a favorable pharmacodynamic response.

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“…The best sensitivity obtained in those assays was 1 ng/mL in plasma with a plasma volume of 150-µL 14,15 or 0.1 ng/mL with a plasma volume of 500-µL using LC-MS/MS detection with an API-5000 mass spectrometer 17 . Basic pH mobile phases were used in these two assays 14,15,16 .…”

Section: Historical Assay Challengesmentioning

confidence: 99%

Selective Reaction Monitoring of Negative Electrospray Ionization Acetate Adduct Ions for the Bioanalysis of Dapagliflozin in Clinical Studies

et al. 2015

Anal. Chem.

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Dapagliflozin (Farxiga), alone, or in the fixed dose combination with metformin (Xigduo), is an orally active, highly selective, reversible inhibitor of sodium-glucose cotransporter type 2 (SGLT2) that is marketed in United States, Europe, and many other countries for the treatment of type 2 diabetes mellitus. Here we report a liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalytical assay of dapagliflozin in human plasma. A lower limit of quantitation (LLOQ) at 0.2 ng/mL with 50 μL of plasma was obtained, which reflects a 5-fold improvement of the overall assay sensitivity in comparison to the previous most sensitive assay using the same mass spectrometry instrumentation. In this new assay, acetate adduct ions in negative electrospray ionization mode were used as the precursor ions for selective reaction monitoring (SRM) detection. Sample preparation procedures and LC conditions were further developed to enhance the column life span and achieve the separation of dapagliflozin from potential interferences, especially its epimers. The assay also quantifies dapagliflozin's major systemic circulating glucuronide metabolite, BMS-801576, concentrations in human plasma. The assay was successfully transferred to contract research organizations (CROs), validated, and implemented for the sample analysis of pediatric and other critical clinical studies. This assay can be widely used for bioanalytical support of future clinical studies for the newly approved drug Farxiga or any combination therapy containing dapagliflozin.

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Pharmacokinetics and pharmacodynamics of dapagliflozin, a novel selective inhibitor of sodium-glucose co-transporter type 2, in Japanese subjects without and with type 2 diabetes mellitus

Abstract: Dapagliflozin was well tolerated and showed predictable dose-proportional PK and PD parameters in both healthy and T2DM Japanese subjects.

Cited by 101 publications

References 13 publications

Dapagliflozin Binds Specifically to Sodium-Glucose Cotransporter 2 in the Proximal Renal Tubule

Dapagliflozin Binds Specifically to Sodium-Glucose Cotransporter 2 in the Proximal Renal Tubule

Preclinical Species and Human Disposition of PF-04971729, a Selective Inhibitor of the Sodium-Dependent Glucose Cotransporter 2 and Clinical Candidate for the Treatment of Type 2 Diabetes Mellitus

Selective Reaction Monitoring of Negative Electrospray Ionization Acetate Adduct Ions for the Bioanalysis of Dapagliflozin in Clinical Studies

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