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Clinical Pharmacokinetics

, Volume 43, Issue 2, pp 97–120 | Cite as

Clinical Pharmacokinetics of Nateglinide

A Rapidly-Absorbed, Short-Acting Insulinotropic Agent
  • James F. McLeod
Review Article

Abstract

The prevalence and medical and economic impact of type 2 diabetes mellitus is increasing in Western societies. New agents have been developed that act primarily to reduce postprandial glucose excursions, which may be of particular significance now that postprandial glucose excursions are known to be correlated with cardiovascular morbidity and mortality.

Nateglinide is a phenylalanine derivative that blocks K+ channels in pancreatic β-cells, facilitating insulin secretion. Nateglinide sensitises β-cells to ambient glucose, reducing the glucose concentration needed to stimulate insulin secretion. The pharmacokinetics of nateglinide are characterised by rapid absorption and elimination, with good (73%) bioavailability. Nateglinide is more rapidly absorbed when given 0–30 minutes prior to meal ingestion than if given during the meal. Nateglinide is extensively metabolised, primarily by cytochrome P450 2C9, and eliminated primarily by the kidney. Nateglinide pharmacokinetics are linear over the dose range 60–240mg. No significant pharmacokinetic alterations occur in renally impaired patients, in the elderly, or in mildly hepatically impaired patients.

Nateglinide administered prior to meals stimulates rapid, short-lived insulin secretion in a dose-dependent manner, thus decreasing mealtime plasma glucose excursions. Its effects on insulin secretion are synergistic with those of a meal. With increasing nateglinide doses, the risk of hypoglycaemia also increases, but its incidence is low. Even if a meal is missed, and the patient skips the dose of nateglinide (as recommended in the event of a missed meal), the incidence of subsequent hypoglycaemia remains low compared with long-acting agents. The postprandial insulinotropic effects of nateglinide are more rapid than those of repaglinide and more rapid and greater than those of glibenclamide (glyburide), while producing less prolonged insulin exposure and less risk of delayed hypoglycaemia. Further investigation is required to determine if nateglinide inhibition of postprandial glucose excursions will help to prevent diabetic complications or preserve pancreatic β-cell function.

Keywords

Metformin Insulin Secretion Glibenclamide Troglitazone Repaglinide 
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.

Notes

Acknowledgements

Sincerest thanks are extended to Cynthia Lategan, Pratapa Prasad and Monica Ligueros-Saylan for their contributions to the preparation and review of the manuscript. The author has provided no information on sources of funding or on conflicts of interest directly relevant to the content of this review.

References

  1. 1.
    Amos AF, McCarty DJ, Zimmet P. The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabet Med 1997; 14 Suppl. 5: S1–85PubMedGoogle Scholar
  2. 2.
    Harris MI. Epidemiologic studies on the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM). Clin Invest Med 1995; 18(4): 231–9PubMedGoogle Scholar
  3. 3.
    Mokdad AH, Ford ES, Bowman BA, et al. Diabetes trends in the US: 1990–1998. Diabetes Care 2000; 23(9): 1278–83PubMedCrossRefGoogle Scholar
  4. 4.
    Mokdad AH, Bowman BA, Ford ES, et al. The continuing epidemics of obesity and diabetes in the United States. JAMA 2001; 286(10): 1195–200PubMedCrossRefGoogle Scholar
  5. 5.
    Dornhorst A. Insulinotropic meglitinide analogues. Lancet 2001; 358(9294): 1709–16PubMedCrossRefGoogle Scholar
  6. 6.
    Schrand LM, Spanheimer RG. Nateglinide: a new member of the meglitinide family for postprandial glucose control in type 2 diabetes. Formulary 2000; 35: 798–811Google Scholar
  7. 7.
    Lyakhovetsky A, Rivkin K, Rozenfeld V. Drug forecast: nateglinide in the management of diabetes mellitus. Pharmacy Ther 2001; 26(6): 324–8Google Scholar
  8. 8.
    Dunn CJ, Faulds D. Nateglinide. Drugs 2000; 60(3): 607–15PubMedCrossRefGoogle Scholar
  9. 9.
    Zimmerman BR. Diagnosis and classifications. In: Zimmerman BR, editor. Medical management of type 2 diabetes. Alexandria (VA): American Diabetes Association, 1998: 2–61Google Scholar
  10. 10.
    ECDCDM. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1999; 22 Suppl. 1: S5–22Google Scholar
  11. 11.
    UKPDSG. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352(9131): 837–53CrossRefGoogle Scholar
  12. 12.
    UKPDSG. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes. Lancet 1998; 352(9131): 854–65CrossRefGoogle Scholar
  13. 13.
    Halas CJ. Nateglinide: a new member of the meglitinide family for postprandial glucose control in type 2 diabetes. Am J Health Syst Pharm 2001; 58(13): 1200–5PubMedGoogle Scholar
  14. 14.
    Ceriello A. The emerging role of post-prandial hyperglycaemic spikes in the pathogenesis of diabetic complications. Diabet Med 1998; 15(3): 188–93PubMedCrossRefGoogle Scholar
  15. 15.
    Hanefeld M, Fischer S, Julius U, et al. Risk factors for myocardial infarction and death in newly detected NIDDM: the Diabetes Intervention Study, 11-year follow-up. Diabetologia 1996; 39(12): 1577–83PubMedCrossRefGoogle Scholar
  16. 16.
    DECODESG. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria: The DECODE Study Group: European Diabetes Epidemiology Group. Diabetes Epidemiology. Collaborative analysis of diagnostic criteria in Europe. Lancet 1999; 354(9179): 617–21CrossRefGoogle Scholar
  17. 17.
    Rodriguez BL, Lau N, Burchfiel CM, et al. Glucose intolerance and 23-year risk of coronary heart disease and total mortality: the Honolulu Heart Program. Diabetes Care 1999; 22(8): 1262–5PubMedCrossRefGoogle Scholar
  18. 18.
    Shaw JE, Hodge AM, de Courten M, et al. Isolated post-challenge hyperglycaemia confirmed as a risk factor for mortality. Diabetologia 1999; 42(9): 1050–4PubMedCrossRefGoogle Scholar
  19. 19.
    Tominaga M, Eguchi H, Manaka H, et al. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose: The Funagata Diabetes Study. Diabetes Care 1999; 22(6): 920–4PubMedCrossRefGoogle Scholar
  20. 20.
    Barrett-Connor E, Ferrara A. Isolated postchallenge hyperglycemia and the risk of fatal cardiovascular disease in older women and men: The Rancho Bernardo Study. Diabetes Care 1998; 21(8): 1236–9PubMedCrossRefGoogle Scholar
  21. 21.
    Landgraf R. Meglitinide analogues in the treatment of type 2 diabetes mellitus. Drugs Aging 2000; 17(5): 411–25PubMedCrossRefGoogle Scholar
  22. 22.
    Pratley RE, Foley JE, Dunning BE. Rapid acting insulinotropic agents: restoration of early insulin secretion as a physiologic approach to improve glucose control. Curr Pharm Des 2001; 7(14): 1375–97PubMedCrossRefGoogle Scholar
  23. 23.
    Levien TL, Baker DE, Campbell RK, et al. Nateglinide therapy for type 2 diabetes mellitus. Ann Pharmacother 2001; 35(11): 1426–34PubMedCrossRefGoogle Scholar
  24. 24.
    Weaver ML, Orwig BA, Rodriguez LC, et al. Pharmacokinetics and metabolism of nateglinide in humans. Drug Metab Dispos 2001; 29(4 Pt 1): 415–21PubMedGoogle Scholar
  25. 25.
    Novartis Pharmaceuticals. Starlix® (nateglinide tablets): prescribing information. East Hanover (NJ): Novartis Pharmaceuticals Corporation, November 2002Google Scholar
  26. 26.
    Takiguchi K, Ishihara H, Ohashi Y, et al. Escalating dose study of a novel non-SU agent, A-4166, in type 2 diabetes. Nihon Univ J Med 2000; 42: 31–45Google Scholar
  27. 27.
    Devineni D, McLeod J, Hirschberg Y, et al. The pharmacokinetics and pharmacodynamics of nateglinide in relation to meal timing in non-insulin dependent diabetes mellitus (NIDDM) subjects [abstract]. AAPS PharmSci 1998; 11(1): S143Google Scholar
  28. 28.
    Luzio SD, Anderson DM, Owens DR. Effects of timing of administration and meal composition on the pharmacokinetic and pharmacodynamic characteristics of the short-acting oral hypoglycemic agent nateglinide in healthy subjects. J Clin Endocrinol Metab 2001; 86(10): 4874–80PubMedCrossRefGoogle Scholar
  29. 29.
    Karara AH, Dunning BE, McLeod JF. The effect of food on the oral bioavailability and the pharmacodynamic actions of the insulinotropic agent nateglinide in healthy subjects. J Clin Pharmacol 1999; 39(2): 172–9PubMedCrossRefGoogle Scholar
  30. 30.
    Novo Nordisk Pharmaceuticals. Prandin® (repaglinide) tablets: prescribing information. Princeton (NJ): Novo Nordisk Pharmaceuticals, Inc., October 1998Google Scholar
  31. 31.
    Pharmacia & Upjohn. Micronase® (glyburide tablets): prescribing information. Kalamazoo (MI): Pharmacia & Upjohn Co., January 2000Google Scholar
  32. 32.
    Prendergast BD. Glyburide and glipizide, second-generation oral sulfonylurea hypoglycemic agents. Clin Pharm 1984; 3(5): 473–85PubMedGoogle Scholar
  33. 33.
    Sunnybrook Pharmacy Department. Pharmacokinetic summary of glyburide [online]. Available from URL: http://www.icomm.ca/shsc/kinetics/glyburid.html [Accessed 2003 Oct 15]
  34. 34.
    Rydberg T, Jonsson A, Melander A. Comparison of the kinetics of glyburide and its active metabolites in humans. J Clin Pharm Ther 1995; 20(5): 283–95PubMedCrossRefGoogle Scholar
  35. 35.
    Takesada H, Matsuda K, Ohtake R, et al. Structure determination of metabolites isolated from urine and bile after administration of AY4166, a novel D-phenylalanine-derivative hypoglycemic agent. Bioorg Med Chem 1996; 4(10): 1771–81PubMedCrossRefGoogle Scholar
  36. 36.
    Karara AH, Lee J, McLeod JF. The correlation between the pharmacodynamics and the pharmacokinetics of nateglinide in healthy adults after a single intravenous or oral dose [abstract]. AAPS PharmSci 1998; 11(1): 2022Google Scholar
  37. 37.
    Gribble FM, Manley SE, Levy JC. Randomized dose ranging study of the reduction of fasting and postprandial glucose in type 2 diabetes by nateglinide (A-4166). Diabetes Care 2001; 24(7): 1221–5PubMedCrossRefGoogle Scholar
  38. 38.
    Kikuchi M. Modulation of insulin secretion in non-insulin-dependent diabetes mellitus by two novel oral hypoglycaemic agents, NN623 and A4166. Diabet Med 1996; 13(9 Suppl. 6): S151–5PubMedGoogle Scholar
  39. 39.
    East Hanover, NJ: Novartis Pharmaceuticals, 1999. (Data on file)Google Scholar
  40. 40.
    Zhou H, Walter YH, Smith HT, et al. Nateglinide, a novel antidiabetic agent: lack of pharmacokinetic interaction with digoxin. Clinical Drug Investigation 2000; 19 Suppl. 1: 465–71CrossRefGoogle Scholar
  41. 41.
    Anderson D, Shelley S, Crick N, et al. A three-way cross over study to evaluate the pharmacokinetic interaction between nateglinide and diclofenac in healthy volunteers. Int J Clin Pharmacol Ther 2002 Oct; 40(10): 457–64PubMedGoogle Scholar
  42. 42.
    Leemann T, Transon C, Dayer P. Cytochrome P450TB (CYP2C): a major monooxygenase catalyzing diclofenac 4′-hydroxylation in human liver. Life Sci 1993; 52(1): 29–34PubMedCrossRefGoogle Scholar
  43. 43.
    Anderson DM, Shelley S, Crick N, et al. No effect of the novel antidiabetic agent nateglinide on the pharmacokinetics and anticoagulant properties of warfarin in healthy volunteers. J Clin Pharmacol 2002; 42: 1358–65PubMedCrossRefGoogle Scholar
  44. 44.
    Bristol-Myers Squibb. Coumadin® (warfarin sodium): prescribing information. Princeton (NJ): Bristol-Myers Squibb, June 2002Google Scholar
  45. 45.
    Zhou H, Walter Y, Smith HT, et al. Nateglinide, a new mealtime glucose regulator: lack of pharmacokinetic interaction with digoxin in healthy volunteers. Clin Drug Invest 2000; 19(6): 465–71CrossRefGoogle Scholar
  46. 46.
    Hirschberg Y, Karara AH, Pietri AO, et al. Improved control of mealtime glucose excursions with coadministration of nateglinide and metformin. Diabetes Care 2000; 23(3): 349–53PubMedCrossRefGoogle Scholar
  47. 47.
    East Hanover, NJ: Novartis Pharmaceuticals, 1998. (Data on file)Google Scholar
  48. 48.
    Ishii T, Yamakita T, Yamagami K, et al. Nateglinide is safe and efficacious in lowering postprandial blood glucose in type 2 diabetic patients with various degree of renal function [abstract]. Diabetes 2001; 50: A118CrossRefGoogle Scholar
  49. 49.
    Devineni D, Walter Y, Smith HT, et al. Pharmacokinetics of nateglinide in renally impaired diabetic patients. J Clin Pharmacol 2003 Feb; 43(2): 163–70PubMedCrossRefGoogle Scholar
  50. 50.
    Choudhury S, Hirschberg Y, Filipek R, et al. Single-dose pharmacokinetics of nateglinide in subjects with hepatic cirrhosis. J Clin Pharmacol 2000; 40(6): 634–40PubMedCrossRefGoogle Scholar
  51. 51.
    Hanefeld M, Bouter KP, Dickinson S, et al. Rapid and short-acting mealtime insulin secretion with nateglinide controls both prandial and mean glycemia. Diabetes Care 2000; 23(2): 202–7PubMedCrossRefGoogle Scholar
  52. 52.
    Uto Y, Teno S, Iwamoto Y, et al. Nateglinide improves the early phase of insulin secretion and postprandial hyperglycemia in patients with type 2 diabetes [abstract]. Diabetes Res 2000; 50 Suppl. 1: S69CrossRefGoogle Scholar
  53. 53.
    Hoyer M, Mallows S, Dickinson S, et al. Nateglinide reduces mean glycemia in diet- and previously treated type 2 diabetic patients [abstract]. Diabetes Res 2000; 50 Suppl. 1: S72CrossRefGoogle Scholar
  54. 54.
    Iwasaki K, Okubo M, Ogawa A, et al. Nateglinide improves glycemic control in type 2 diabetes. Diabetes 2001; 50: A438Google Scholar
  55. 55.
    Mori Y, Ishii H, Hikita M, et al. The improvement in early phase of insulin secretion after glucose load with nateglinide in patients with type 2 diabetes [abstract]. Diabetes 2001; 50: A127CrossRefGoogle Scholar
  56. 56.
    Walter YH, Spratt DI, Garreffa S, et al. Mealtime glucose regulation by nateglinide in type-2 diabetes mellitus. Eur J Clin Pharmacol 2000; 56(2): 129–33PubMedCrossRefGoogle Scholar
  57. 57.
    Keilson L, Mather S, Walter YH, et al. Synergistic effects of nateglinide and meal administration on insulin secretion in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2000; 85(3): 1081–6PubMedCrossRefGoogle Scholar
  58. 58.
    Ligueros-Saylan M, Khalilieh S, Lee J, et al. Nateglinide has a low hypoglycemic potential in a missed-meal situation [abstract]. Diabetes 2000; 49 Suppl. 1: A360Google Scholar
  59. 59.
    Ferner RE, Neil AW. Sulphonylureas and hypoglycaemia. BMJ 1988; 296: 949–50PubMedCrossRefGoogle Scholar
  60. 60.
    Seltzer HS. Drug induced hypoglycemia: a review of 1418 cases. Endocrinol Metab Clin North Am 1989; 18(1): 163–83PubMedGoogle Scholar
  61. 61.
    Dills DG, Schneider J. Clinical evaluation of glimepiride versus glibenclamide in NIDDM in a double-blind comparative study. Horm Metab Res 1996; 28: 426–9PubMedCrossRefGoogle Scholar
  62. 62.
    Stahl M, Berger W. Higher incidence of severe hypoglycaemia leading to hospital admission in type 2 diabetic patients treated with long-acting versus short-acting sulphonylureas. Diabet Med 1999; 16(7): 586–90PubMedCrossRefGoogle Scholar
  63. 63.
    Grodsky GM. A new phase of insulin secretion: how will it contribute to our understanding of beta-cell function?. Diabetes 1989; 38(6): 673–8PubMedCrossRefGoogle Scholar
  64. 64.
    Ward WK, Beard JC, Halter JB, et al. Pathophysiology of insulin secretion in non-insulin-dependent diabetes mellitus. Diabetes Care 1984; 7(5): 491–502PubMedCrossRefGoogle Scholar
  65. 65.
    Kahn SE, Montgomery B, Howell W, et al. Importance of early phase insulin secretion to intravenous glucose tolerance in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab 2001 Dec; 86(12): 5824–9PubMedCrossRefGoogle Scholar
  66. 66.
    Whitelaw DC, Clark PM, Smith JM, et al. Effects of the new oral hypoglycaemic agent nateglinide on insulin secretion in type 2 diabetes mellitus. Diabet Med 2000; 17(3): 225–9PubMedCrossRefGoogle Scholar
  67. 67.
    Foley J, Wang S, Hu S. Glucose-dependent and glucose sensitizing insulinotropic effects of nateglinide: comparison to glyburide and repaglinide [abstract]. Diabetologia 2000; 43 Suppl. 1: A127Google Scholar
  68. 68.
    DeFronzo RA, Simonson D, Ferrannini E. Hepatic and peripheral insulin resistance: a common feature of type 2 (non-insulin-dependent) and type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1982; 23(4): 313–9PubMedCrossRefGoogle Scholar
  69. 69.
    Jeng CY, Sheu WH, Fuh MM, et al. Relationship between hepatic glucose production and fasting plasma glucose concentration in patients with NIDDM. Diabetes 1994; 43(12): 1440–4PubMedCrossRefGoogle Scholar
  70. 70.
    Stumvoll M, Meyer C, Mitrakou A, et al. Renal glucose production and utilization: new aspects in humans. Diabetologia 1997; 40(7): 749–57PubMedCrossRefGoogle Scholar
  71. 71.
    Mitrakou A, Kelley D, Mokan M, et al. Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med 1992; 326(1): 22–9PubMedCrossRefGoogle Scholar
  72. 72.
    Kelley D, Mokan M, Veneman T. Impaired postprandial glucose utilization in non-insulin-dependent diabetes mellitus. Metabolism 1994; 43(12): 1549–57PubMedCrossRefGoogle Scholar
  73. 73.
    Horton ES, Clinkingbeard C, Gatlin M, et al. Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetes. Diabetes Care 2000; 23(11): 1660–5PubMedCrossRefGoogle Scholar
  74. 74.
    Marre M, Whatmough J, Pongowski M, et al. Nateglinide added to metformin offers safe and effective treatment for type 2 diabetes [abstract]. Diabetes 2000; 49 Suppl. 1: A361Google Scholar
  75. 75.
    Rosenstock J, Gatlin M, Mallows S, et al. Nateglinide improves glycemic control alone and in combination with troglitazone in patients with type 2 diabetes [abstract]. Diabetes 2000; 49 Suppl. I: A123Google Scholar
  76. 76.
    Mallows S, Guitard C, Shen S, et al. Nateglinide is effective and safe in elderly patients with type 2 diabetes. Diabetes Res 2000; 50 Suppl. 1: S73CrossRefGoogle Scholar
  77. 77.
    Hu S, Wang S, Fanelli B, et al. Pancreatic beta-cell K (ATP) channel activity and membrane-binding studies with nateglinide: a comparison with sulfonylureas and repaglinide. J Pharmacol Exp Ther 2000; 293(2): 444–52PubMedGoogle Scholar
  78. 78.
    Kalbag JB, Walter YH, Nedelman JR, et al. Mealtime glucose regulation with nateglinide in healthy volunteers: comparison with repaglinide and placebo. Diabetes Care 2001; 24(1): 73–7PubMedCrossRefGoogle Scholar
  79. 79.
    Walter Y, Brookman L, Ma P, et al. Reduced risk of delayed hypoglycemia with nateglinide compared with repaglinide [abstract]. Diabetes 2000; 49 Suppl. 1: A128–9Google Scholar
  80. 80.
    Hollander PA, Schwartz SL, Gatlin MR, et al. Importance of early insulin secretion: comparison of nateglinide and glyburide in previously diet-treated patients with type 2 diabetes. Diabetes Care 2001; 24(6): 983–8PubMedCrossRefGoogle Scholar
  81. 81.
    Horton ES, Gatlin M, Dunn FL, et al. Risks/benefits of achieving HbA1c goals with nateglinide [abstract]. Diabetes 2001; 50: A438Google Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • James F. McLeod
    • 1
  1. 1.Novartis PharmaceuticalsOne Health PlazaEast HanoverUSA

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