Clinical Pharmacokinetics

, Volume 53, Issue 1, pp 17–27 | Cite as

Clinical Pharmacokinetics and Pharmacodynamics of Dapagliflozin, a Selective Inhibitor of Sodium-Glucose Co-transporter Type 2

  • Sreeneeranj KasichayanulaEmail author
  • Xiaoni Liu
  • Frank LaCreta
  • Steven C. Griffen
  • David W. Boulton
Review Article


Sodium-glucose co-transporter 2 (SGLT2) is predominantly expressed in the S1 segment of the proximal tubule of the kidney and is the major transporter responsible for mediating renal glucose reabsorption. Dapagliflozin is an orally active, highly selective SGLT2 inhibitor that improves glycemic control in patients with type 2 diabetes mellitus (T2DM) by reducing renal glucose reabsorption leading to urinary glucose excretion (glucuresis). Orally administered dapagliflozin is rapidly absorbed generally achieving peak plasma concentrations within 2 h. Dose-proportional systemic exposure to dapagliflozin has been observed over a wide dose range (0.1–500 mg) with an oral bioavailability of 78 %. Dapagliflozin has extensive extravascular distribution (mean volume of distribution of 118 L). Dapagliflozin metabolism occurs predominantly in the liver and kidneys by uridine diphosphate-glucuronosyltransferase-1A9 to the major metabolite dapagliflozin 3-O-glucuronide (this metabolite is not an SGLT2 inhibitor at clinically relevant exposures). Dapagliflozin is not appreciably cleared by renal excretion (<2 % of dose is recovered in urine as parent). Dapagliflozin 3-O-glucuronide elimination occurs mainly via renal excretion, with 61 % of a dapagliflozin dose being recovered as this metabolite in urine. The half-life for orally administered dapagliflozin 10 mg was 12.9 h. Maximal increases in urinary glucose excretion were seen at doses ≥20 mg/day in patients with T2DM. No clinically relevant differences were observed in dapagliflozin exposure with respect to age, race, sex, body weight, food, or presence of T2DM. Pharmacodynamic changes are dependent on plasma glucose and renal function, and decreases in urinary glucose excretion were observed due to the lower filtered load (plasma glucose × glomerular filtration rate) in healthy volunteers compared to subjects with T2DM. After multiple doses of dapagliflozin, urinary glucose excretion was associated with dose-related decreases in plasma glucose parameters in subjects with T2DM. Patients with severe renal or hepatic impairment show higher systemic exposure to dapagliflozin. No clinically relevant drug interactions were observed that would necessitate dose adjustment of dapagliflozin when administered with other antidiabetic or cardiovascular medications, as well as drugs that could potentially influence dapagliflozin metabolism.


Valsartan Sitagliptin Bumetanide Mefenamic Acid Biopharmaceutics Classification System 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Medical writing assistance was provided by Ray Ashton and Karen Pemberton, PhD of PPSI (a PAREXEL company) and was funded by AstraZeneca and Bristol-Myers Squibb. All authors are employees of Bristol-Myers Squibb.


  1. 1.
    International Diabetes Foundation. The global burden. International Diabetes Foundation Web site. Accessed 4 Mar 2013.
  2. 2.
    World Diabetes Foundation. Diabetes facts. World Diabetes Foundation Web site. Accessed 4 Mar 2013.
  3. 3.
    World Health Organisation. Global strategy on diet, physical activity and health. World Health Organisation Web site. Accessed 4 Mar 2013.
  4. 4.
    American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care. 2013;36:S11–66.CrossRefGoogle Scholar
  5. 5.
    Braga MF, Casanova A, Teoh H, et al. Poor achievement of guidelines-recommended targets in type 2 diabetes: findings from a contemporary prospective cohort study. Int J Clin Pract. 2012;66:457–64.PubMedCrossRefGoogle Scholar
  6. 6.
    Hermans MP, Brotons C, Elisaf M, et al. Optimal type 2 diabetes mellitus management: the randomised controlled OPTIMISE benchmarking study: baseline results from six European countries. Eur J Prev Cardiol. 2012. doi: 10.1177/2047487312449414.
  7. 7.
    Wong ND, Glovaci D, Wong K, et al. Global cardiovascular disease risk assessment in United States adults with diabetes. Diab Vasc Dis Res. 2012;9:146–52.PubMedCrossRefGoogle Scholar
  8. 8.
    Marsenic O. Glucose control by the kidney: an emerging target in diabetes. Am J Kidney Dis. 2009;53:875–83.PubMedCrossRefGoogle Scholar
  9. 9.
    Kim Y, Babu AR. Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes. Diabetes Metab Syndr Obes. 2012;5:313–27.PubMedCentralPubMedGoogle Scholar
  10. 10.
    Meng W, Ellsworth BA, Nirschl AA, et al. Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J Med Chem. 2008;51:1145–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Ferrannini E, Ramos SJ, Salsali A, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010;33:2217–24.PubMedCrossRefGoogle Scholar
  12. 12.
    List JF, Woo V, Morales E, et al. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care. 2009;32:650–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Bailey CJ, Gross JL, Pieters A, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375:2223–33.PubMedCrossRefGoogle Scholar
  14. 14.
    Wilding JP, Norwood P, T’joen C, et al. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes Care. 2009;32:1656–62.PubMedCrossRefGoogle Scholar
  15. 15.
    Ptaszynska A, Johnsson K, Apanovitch A, et al. Safety of dapagliflozin in clinical trials for T2DM. Diabetes. 2012;61(suppl 1):A258–9.Google Scholar
  16. 16.
    Boulton DW, Kasichayanula S, Keung CF, et al. Simultaneous oral therapeutic and intravenous (1)(4)C-microdoses to determine the absolute oral bioavailability of saxagliptin and dapagliflozin. Br J Clin Pharmacol. 2013;75:763–8.PubMedGoogle Scholar
  17. 17.
    Obermeier M, Yao M, Khanna A, et al. In vitro characterization and pharmacokinetics of dapagliflozin (BMS-512148), a potent sodium-glucose cotransporter type II inhibitor, in animals and humans. Drug Metab Dispos. 2010;38:405–14.PubMedCrossRefGoogle Scholar
  18. 18.
    Zinker B, Ma X, Liu H, et al. Chronic dapagliflozin treatment reduces elevated hepatic glucose production and enhances pancreatic insulin content in male ZDF rats. (Abstract 1031-P). Diabetes. 2011;60(suppl 1):A283.Google Scholar
  19. 19.
    Forxiga: Summary of Product Characteristics. AstraZeneca and Bristol-Myers Squibb. Accessed 8 Apr 2013.
  20. 20.
    Kasichayanula S, Liu X, Zhang W, et al. Effect of a high-fat meal on the pharmacokinetics of dapagliflozin, a selective SGLT2 inhibitor, in healthy subjects. Diabetes Obes Metab. 2011;13:770–3.PubMedCrossRefGoogle Scholar
  21. 21.
    Kasichayanula S, Liu X, Zhang W, et al. Influence of hepatic impairment on the pharmacokinetics and safety profile of dapagliflozin: an open-label, parallel-group, single-dose study. Clin Ther. 2011;33:1798–808.PubMedCrossRefGoogle Scholar
  22. 22.
    Kasichayanula S, Liu X, Benito MP, et al. The influence of kidney function on dapagliflozin exposure, metabolism, and efficacy in healthy subjects and in patients with type 2 diabetes mellitus. Br J Clin Pharmacol. 2013;76(3):432–44. doi: 10.1111/bcp.12056.Google Scholar
  23. 23.
    Kasichayanula S, Yao M, Vachharajani M, et al. Disposition and Mass Balance of [14C]-dapagliflozin after single oral dose in healthy male volunteers. AAPS J. 2008;10(S2).Google Scholar
  24. 24.
    Dostalek M, Court MH, Hazarika S, et al. Diabetes mellitus reduces activity of human UDP-glucuronosyltransferase 2B7 in liver and kidney leading to decreased formation of mycophenolic acid acyl-glucuronide metabolite. Drug Metab Dispos. 2011;39:448–55.PubMedCrossRefGoogle Scholar
  25. 25.
    Abdul-Ghani MA, DeFronzo RA. Inhibition of renal glucose reabsorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract. 2008;14:782–90.PubMedCrossRefGoogle Scholar
  26. 26.
    Vallon V, Platt KA, Cunard R, et al. SGLT2 mediates glucose reabsorption in the early proximal tubule. J Am Soc Nephrol. 2011;22:104–12.PubMedCrossRefGoogle Scholar
  27. 27.
    Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91:733–94.PubMedCrossRefGoogle Scholar
  28. 28.
    Hummel CS, Lu C, Liu J, et al. Structural selectivity of human SGLT inhibitors. Am J Physiol Cell Physiol. 2012;302:C373–82.PubMedCrossRefGoogle Scholar
  29. 29.
    Komoroski B, Vachharajani N, Feng Y, et al. Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus. Clin Pharmacol Ther. 2009;85:513–9.PubMedCrossRefGoogle Scholar
  30. 30.
    DeFronzo RA, Hompesch M, Kasichayanula S, et al. Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care. 2013 [Epub ahead of print].Google Scholar
  31. 31.
    Komoroski B, Vachharajani N, Boulton D, et al. Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Ther. 2009;85:520–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Carlson GF, Tou CK, Parikh S, et al. Evaluation of the effect of dapagliflozin on cardiac repolarization: a thorough QT/QTc study. Diabetes Ther. 2011;2:123–32.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Kasichayanula S, Chang M, Hasegawa M, et al. 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. Diabetes Obes Metab. 2011;13:357–65.PubMedCrossRefGoogle Scholar
  34. 34.
    Yang L, Li H, Li H, et al. Pharmacokinetic and pharmacodynamic properties of single- and multiple-dose of dapagliflozin, a selective inhibitor of SGLT2, in healthy Chinese subjects. Clin Ther. 2013;35(8):1211–22.e2.Google Scholar
  35. 35.
    Kasichayanula S, Liu X, Shyu WC, et al. Lack of pharmacokinetic interaction between dapagliflozin, a novel sodium-glucose transporter 2 inhibitor, and metformin, pioglitazone, glimepiride or sitagliptin in healthy subjects. Diabetes Obes Metab. 2011;13:47–54.PubMedCrossRefGoogle Scholar
  36. 36.
    Imamura A, Kusunoki M, Ueda S, et al. Impact of voglibose on the pharmacokinetics of dapagliflozin in Japanese patients with type 2 diabetes. Diabetes Ther. 2013;4(1):41–9.Google Scholar
  37. 37.
    Kasichayanula S, Chang M, Liu X, et al. Lack of pharmacokinetic interactions between dapagliflozin and simvastatin, valsartan, warfarin, or digoxin. Adv Ther. 2012;29:163–77.PubMedCrossRefGoogle Scholar
  38. 38.
    Wilcox CS, Liu X, Kasichayanula S, et al. Evaluation of interactions of dapagliflozin and bumetanide. Presented at: American Society of Nephrology, Denver (2010).Google Scholar
  39. 39.
    Kasichayanula S, Liu X, Griffen SC, et al. Effects of rifampin and mefenamic acid on the pharmacokinetics and pharmacodynamics of dapagliflozin. Diabetes Obes Metab. 2013;15:280–3.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Sreeneeranj Kasichayanula
    • 1
    Email author
  • Xiaoni Liu
    • 1
  • Frank LaCreta
    • 1
  • Steven C. Griffen
    • 1
  • David W. Boulton
    • 1
  1. 1.Bristol-Myers Squibb CoPrincetonUSA

Personalised recommendations