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Effect of Diabetes Mellitus on Pharmacokinetic and Pharmacodynamic Properties of Drugs

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Abstract

The effects of diabetes mellitus on the pharmacokinetics and pharmacodynamics of drugs have been well described in experimental animal models; however, only minimal data exist for humans and the current knowledge regarding the effects of diabetes on these properties remains unclear. Nevertheless, it has been observed that the pharmacokinetics and pharmacodynamics of drugs are changed in subjects with diabetes. It has been reported that diabetes may affect the pharmacokinetics of various drugs by affecting (i) absorption, due to changes in subcutaneous adipose blood flow, muscle blood flow and gastric emptying; (ii) distribution, due to non-enzymatic glycation of albumin; (iii) biotransformation, due to regulation of enzymes/transporters involved in drug biotransformation; and (iv) excretion, due to nephropathy. Previously published data also suggest that diabetes-mediated changes in the pharmacokinetics of a particular drug cannot be translated to others.

Although clinical studies exploring the effect of diabetes on pharmacodynamics are still very limited, there is evidence that disease-mediated effects are not limited only to pharmacokinetics but also alter pharmacodynamics. However, for many drugs it remains unclear whether these influences reflect diabetes-mediated changes in pharmacokinetics rather than pharmacodynamics. In addition, even though diabetes-mediated pharmacokinetics and pharmacodynamics might be anticipated, it is important to study the effect on each drug and not generalize from observed data.

The available data indicate that there is a significant variability in drug response in diabetic subjects. The discrepancies between individual clinical studies as well as between ex vivo and clinical studies are probably due to (i) the restricted and focused population of subjects in clinical studies; (ii) failure to consider type, severity and duration of the disease; (iii) histopathological characteristics generally being missing; and (iv) other factors such as varying medication use, dietary protein intake, age, sex and obesity. The obesity epidemic in the developed world has also inadvertently influenced the directions of pharmacological research.

This review attempts to map new information gained since Gwilt published his paper in Clinical Pharmacokinetics in 1991. Although a large body of research has been conducted and significant progress has been made, we still have to conclude that the available information regarding the effect of diabetes on pharmacokinetics and pharmacodynamics remains unclear and further clinical studies are required before we can understand the clinical significance of the effect. An understanding of diabetes-mediated changes as well as of the source of the variability should lead to the improvement of the medical management and clinical outcomes in patients with this widespread disease.

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References

  1. Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004 May; 27(5): 1047–53

    Article  PubMed  Google Scholar 

  2. International Diabetes Federation Task Force on Diabetes Health Economy. Diabetes heath economics: facts, figures, and forecasts. Brussels: International Diabetes Federation, 1997

    Google Scholar 

  3. King H, Aubert RE, Herman WH. Global burden of diabetes, 1995–2025: prevalence, numerical estimates, and projections. Diabetes Care 1998 Sep; 21(9): 1414–31

    Article  CAS  PubMed  Google Scholar 

  4. Rossing P, de Zeeuw D. Need for better diabetes treatment for improved renal outcome. Kidney Int Suppl 2011 Mar; (120): S28–32

    Article  CAS  Google Scholar 

  5. King H, Rewers M. Global estimates for prevalence of diabetes mellitus and impaired glucose tolerance in adults: WHO Ad Hoc Diabetes Reporting Group. Diabetes Care 1993 Jan; 16(1): 157–77

    Article  CAS  PubMed  Google Scholar 

  6. Arslanian S. Type 2 diabetes in children: clinical aspects and risk factors. Horm Res 2002; 57 Suppl. 1: 19–28

    CAS  PubMed  Google Scholar 

  7. World Health Organization. Diabetes fact sheet no. 312, August 2011 [online]. Available from URL: http://www.who.int/mediacentre/factsheets [Accessed 2012 May 5]

  8. Morwessel NJ. The genetic basis of diabetes mellitus. AACN Clin Issues 1998 Nov; 9(4): 539–54

    Article  CAS  PubMed  Google Scholar 

  9. Herder C, Karakas M, Koenig W. Biomarkers for the prediction of type 2 diabetes and cardiovascular disease. Clin Pharmacol Ther 2011 Jul; 90(1): 52–66

    Article  CAS  PubMed  Google Scholar 

  10. Wing RR, Goldstein MG, Acton KJ, et al. Behavioral science research in diabetes: lifestyle changes related to obesity, eating behavior, and physical activity. Diabetes Care 2001 Jan; 24(1): 117–23

    Article  CAS  PubMed  Google Scholar 

  11. Bassuk SS, Manson JE. Epidemiological evidence for the role of physical activity in reducing risk of type 2 diabetes and cardiovascular disease. J Appl Physiol 2005 Sep; 99(3): 1193–204

    Article  PubMed  Google Scholar 

  12. LaMonte MJ, Blair SN, Church TS. Physical activity and diabetes prevention. J Appl Physiol 2005 Sep; 99(3): 1205–13

    Article  PubMed  Google Scholar 

  13. Engelgau MM, Geiss LS, Saaddine JB, et al. The evolving diabetes burden in the United States. Ann Intern Med 2004 Jun 1; 140(11): 945–50

    Article  PubMed  Google Scholar 

  14. Rendell M, Lassek WD, Ross DA, et al. A pharmaceutical profile of diabetic patients. J Chronic Dis 1983; 36(2): 193–202

    Article  CAS  PubMed  Google Scholar 

  15. Isacson D, Stalhammar J. Prescription drug use among diabetics: a population study. J Chronic Dis 1987; 40(7): 651–60

    Article  CAS  PubMed  Google Scholar 

  16. American Diabetes Association. Economic costs of diabetes in the U.S. in 2007 [published erratum appears in Diabetes Care 2008; 31 (6): 1271]. Diabetes Care 2008; 31(3): 596–615

    Article  Google Scholar 

  17. Watkins P. Diabetes and its management. Oxford: Blackwell Publishing, 2003

    Book  Google Scholar 

  18. Aggarwal S. What’s fueling the biotech engine-2010 to 2011. Nat Biotechnol 2011; 29(12): 1083–9

    Article  CAS  PubMed  Google Scholar 

  19. Gwilt PR, Nahhas RR, Tracewell WG. The effects of diabetes mellitus on pharmacokinetics and pharmacodynamics in humans. Clin Pharmacokinet 1991 Jun; 20(6): 477–90

    Article  CAS  PubMed  Google Scholar 

  20. Cashion AK, Holmes SL, Hathaway DK, et al. Gastroparesis following kidney/pancreas transplant. Clin Transplant 2004 Jun; 18(3): 306–11

    Article  CAS  PubMed  Google Scholar 

  21. Zini R, Riant P, Barre J, et al. Disease-induced variations in plasma protein levels: implications for drug dosage regimens (part I). Clin Pharmacokinet 1990 Aug; 19(2): 147–59

    Article  CAS  PubMed  Google Scholar 

  22. Okabe N, Hashizume N. Drug binding properties of glycosylated human serum albumin as measured by fluorescence and circular dichroism. Biol Pharm Bull 1994 Jan; 17(1): 16–21

    Article  CAS  PubMed  Google Scholar 

  23. Wang T, Shankar K, Ronis MJ, et al. Mechanisms and outcomes of drug- and toxicant-induced liver toxicity in diabetes. Crit Rev Toxicol 2007 Jun; 37(5): 413–59

    Article  CAS  PubMed  Google Scholar 

  24. Zhu L. Gastric mucosal blood flow and blood viscosity in patients with diabetes [in Chinese]. Zhonghua Yi Xue Za Zhi 1993 Aug; 73(8): 476–8, 511

    CAS  PubMed  Google Scholar 

  25. Jacobson ED, Chang AC. Comparison of gastrin and histamine on gastric mucosal blood flow. Proc Soc Exp Biol Med 1969 Feb; 130(2): 484–6

    Article  CAS  PubMed  Google Scholar 

  26. Jacobson ED, Linford RH, Grossman MI. Gastric secretion in relation to mucosal blood flow studied by a clearance technic. J Clin Invest 1966 Jan; 45(1): 1–13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Moody FG. Oxygen consumption during thiocyanate inhibition of gastric acid secretion in dogs. Am J Physiol 1968 Jul; 215(1): 127–31

    CAS  PubMed  Google Scholar 

  28. Hasler WL, Coleski R, Chey WD, et al. Differences in intragastric pH in diabetic vs. idiopathic gastroparesis: relation to degree of gastric retention. Am J Physiol Gastrointest Liver Physiol 2008 Jun; 294(6): G1 384–91

    Article  CAS  Google Scholar 

  29. Stacher G. Diabetes mellitus and the stomach. Diabetologia 2001 Sep; 44(9): 1080–93

    Article  CAS  PubMed  Google Scholar 

  30. Samsom M, Bharucha A, Gerich JE, et al. Diabetes mellitus and gastric emptying: questions and issues in clinical practice. Diabetes Metab Res Rev 2009 Sep; 25(6): 502–14

    Article  PubMed  Google Scholar 

  31. Domstad PA, Kim EE, Coupal JJ, et al. Biologic gastric emptying time in diabetic patients, using Tc-99m-labeled resin-oatmeal with and without metoclopramide. J Nucl Med 1980 Nov; 21(11): 1098–100

    CAS  PubMed  Google Scholar 

  32. Horowitz M, McNeil JD, Maddern GJ, et al. Abnormalities of gastric and esophageal emptying in polymyositis and dermatomyositis. Gastroenterology 1986 Feb; 90(2): 434–9

    Article  CAS  PubMed  Google Scholar 

  33. Keshavarzian A, Iber FL, Vaeth J. Gastric emptying in patients with insulin-requiring diabetes mellitus. Am J Gastroenterol 1987 Jan; 82(1): 29–35

    CAS  PubMed  Google Scholar 

  34. Gilbey SG, Watkins PJ. Measurement by epigastric impedance of gastric emptying in diabetic autonomic neuropathy. Diabet Med 1987 Mar–Apr; 4(2): 122–6

    Article  CAS  PubMed  Google Scholar 

  35. Caballero-Plasencia AM, Muros-Navarro MC, Martin-Ruiz JL, et al. Gastroparesis of digestible and indigestible solids in patients with insulin-dependent diabetes mellitus or functional dyspepsia. Dig Dis Sci 1994 Jul; 39(7): 1409–15

    Article  CAS  PubMed  Google Scholar 

  36. Ziegler D, Schadewaldt P, Pour Mirza A, et al. [13C]octanoic acid breath test for non-invasive assessment of gastric emptying in diabetic patients: validation and relationship to gastric symptoms and cardiovascular autonomic function. Diabetologia 1996 Jul; 39(7): 823–30

    Article  CAS  PubMed  Google Scholar 

  37. Lipp RW, Schnedl WJ, Hammer HF, et al. Evidence of accelerated gastric emptying in longstanding diabetic patients after ingestion of a semisolid meal. J Nucl Med 1997 May; 38(5): 814–8

    CAS  PubMed  Google Scholar 

  38. Dutta U, Padhy AK, Ahuja V, et al. Double blind controlled trial of effect of cisapride on gastric emptying in diabetics. Trop Gastroenterol 1999 Jul–Sep; 20(3): 116–9

    CAS  PubMed  Google Scholar 

  39. Loo FD, Palmer DW, Soergel KH, et al. Gastric emptying in patients with diabetes mellitus. Gastroenterology 1984 Mar; 86(3): 485–94

    CAS  PubMed  Google Scholar 

  40. Merio R, Festa A, Bergmann H, et al. Slow gastric emptying in type I diabetes: relation to autonomic and peripheral neuropathy, blood glucose, and glycemic control. Diabetes Care 1997 Mar; 20(3): 419–23

    Article  CAS  PubMed  Google Scholar 

  41. De Block CE, De Leeuw IH, Pelckmans PA, et al. Delayed gastric emptying and gastric autoimmunity in type 1 diabetes. Diabetes Care 2002 May; 25(5): 912–7

    Article  PubMed  Google Scholar 

  42. Meier M, Linke R, Tatsch K, et al. An advanced approach for the assessment of gastric motor function in long-term type 1 diabetes mellitus with and without autonomic neuropathy. Clin Auton Res 2002 Jun; 12(3): 197–202

    Article  PubMed  Google Scholar 

  43. Iber F, Parveen S, Vandrunen M, et al. Relation of symptoms to impaired stomach, small bowel, and colon motility in long-standing diabetes. Dig Dis Sci 1993; 38(1): 45–50

    Article  CAS  PubMed  Google Scholar 

  44. Horowitz M, Harding PE, Maddox AF, et al. Gastric and oesophageal emptying in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1989 Mar; 32(3): 151–9

    Article  CAS  PubMed  Google Scholar 

  45. Wegener M, Borsch G, Schaffstein J, et al. Gastrointestinal transit disorders in patients with insulin-treated diabetes mellitus. Dig Dis 1990; 8(1): 23–36

    Article  CAS  PubMed  Google Scholar 

  46. Cotroneo P, Grattagliano A, Rapaccini GL, et al. Gastric emptying rate and hormonal response in type II diabetics. Diabetes Res 1991 Jun; 17(2): 99–104

    CAS  PubMed  Google Scholar 

  47. Annese V, Bassotti G, Caruso N, et al. Gastrointestinal motor dysfunction, symptoms, and neuropathy in noninsulin-dependent (type 2) diabetes mellitus. J Clin Gastroenterol 1999 Sep; 29(2): 171–7

    Article  CAS  PubMed  Google Scholar 

  48. Chang CS, Kao CH, Wang YS, et al. Discrepant pattern of solid and liquid gastric emptying in Chinese patients with type II diabetes mellitus. Nucl Med Commun 1996 Jan; 17(1): 60–5

    Article  CAS  PubMed  Google Scholar 

  49. Qi HB, Luo JY, Zhu YL, et al. Gastric myoelectrical activity and gastric emptying in diabetic patients with dyspeptic symptoms. World J Gastroenterol 2002 Feb; 8(1): 180–2

    Article  PubMed  PubMed Central  Google Scholar 

  50. Camilleri M. Clinical practice: diabetic gastroparesis. N Engl J Med 2007 Feb 22; 356(8): 820–9

    Article  CAS  PubMed  Google Scholar 

  51. Boas I. Diseases of stomach. Leipzig: Georg Thieme, 1925

    Google Scholar 

  52. Horowitz M, Fraser R. Disordered gastric motor function in diabetes mellitus. Diabetologia 1994 Jun; 37(6): 543–51

    Article  CAS  PubMed  Google Scholar 

  53. Horowitz M, Wishart JM, Jones KL, et al. Gastric emptying in diabetes: an overview. Diabet Med 1996 Sep; 13 (9 Suppl. 5): S16–22

    CAS  PubMed  Google Scholar 

  54. Jones KL, Russo A, Stevens JE, et al. Predictors of delayed gastric emptying in diabetes. Diabetes Care 2001 Jul; 24(7): 1264–9

    Article  CAS  PubMed  Google Scholar 

  55. Kong MF, Horowitz M. Gastric emptying in diabetes mellitus: relationship to blood-glucose control. Clin Geriatr Med 1999 May; 15(2): 321–38

    CAS  PubMed  Google Scholar 

  56. Chang J, Rayner C, Jones K, et al. Diabetic gastroparesis: backwards and forwards. J Gastroenterol Hepatol 2011; 26 Suppl. 1: 46–57

    Article  PubMed  Google Scholar 

  57. Horowitz M, O’Donovan D, Jones KL, et al. Gastric emptying in diabetes: clinical significance and treatment. Diabet Med 2002 Mar; 19(3): 177–94

    Article  CAS  PubMed  Google Scholar 

  58. Naesens M, Verbeke K, Vanrenterghem Y, et al. Effects of gastric emptying on oral mycophenolic acid pharmacokinetics in stable renal allograft recipients. Br J Clin Pharmacol 2007 May; 63(5): 541–7

    Article  CAS  PubMed  Google Scholar 

  59. Bian RW, Lou QL, Gu LB, et al. Delayed gastric emptying is related to cardiovascular autonomic neuropathy in Chinese patients with type 2 diabetes. Acta Gastroenterol Belg 2011 Mar; 74(1): 28–33

    CAS  PubMed  Google Scholar 

  60. Lyrenas EB, Olsson EH, Arvidsson UC, et al. Prevalence and determinants of solid and liquid gastric emptying in unstable type I diabetes: relationship to postprandial blood glucose concentrations. Diabetes Care 1997 Mar; 20(3): 413–8

    Article  CAS  PubMed  Google Scholar 

  61. Wright RA, Clemente R, Wathen R. Diabetic gastroparesis: an abnormality of gastric emptying of solids. Am J Med Sci 1985 Jun; 289(6): 240–2

    Article  CAS  PubMed  Google Scholar 

  62. Troncon LE, Rosa-e-Silva L, Oliveira RB, et al. Abnormal intragastric distribution of a liquid nutrient meal in patients with diabetes mellitus. Dig Dis Sci 1998 Jul; 43(7): 1421–9

    Article  CAS  PubMed  Google Scholar 

  63. Horowitz M, Maddox AF, Wishart JM, et al. Relationships between oesophageal transit and solid and liquid gastric emptying in diabetes mellitus. Eur J Nucl Med 1991; 18(4): 229–34

    Article  CAS  PubMed  Google Scholar 

  64. Nowak TV, Johnson CP, Kalbfleisch JH, et al. Highly variable gastric emptying in patients with insulin dependent diabetes mellitus. Gut 1995 Jul; 37(1): 23–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kong MF, King P, Macdonald IA, et al. Euglycaemic hyperinsulinaemia does not affect gastric emptying in type I and type II diabetes mellitus. Diabetologia 1999 Mar; 42(3): 365–72

    Article  CAS  PubMed  Google Scholar 

  66. Frank JW, Saslow SB, Camilleri M, et al. Mechanism of accelerated gastric emptying of liquids and hyperglycemia in patients with type II diabetes mellitus. Gastroenterology 1995 Sep; 109(3): 755–65

    Article  CAS  PubMed  Google Scholar 

  67. Schwartz JG, Green GM, Guan D, et al. Rapid gastric emptying of a solid pancake meal in type II diabetic patients. Diabetes Care 1996 May; 19(5): 468–71

    Article  CAS  PubMed  Google Scholar 

  68. Rayner CK, Samsom M, Jones KL, et al. Relationships of upper gastrointestinal motor and sensory function with glycemic control. Diabetes Care 2001 Feb; 24(2): 371–81

    Article  CAS  PubMed  Google Scholar 

  69. MacGregor IL, Gueller R, Watts HD, et al. The effect of acute hyperglycemia on gastric emptying in man. Gastroenterology 1976 Feb; 70(2): 190–6

    CAS  PubMed  Google Scholar 

  70. Russo A, Stevens JE, Chen R, et al. Insulin-induced hypoglycemia accelerates gastric emptying of solids and liquids in long-standing type 1 diabetes. J Clin Endocrinol Metab 2005 Aug; 90(8): 4489–95

    Article  CAS  PubMed  Google Scholar 

  71. Asmar M. New physiological effects of the incretin hormones GLP-1 and GIP. Dan Med Bull 2011 Feb; 58(2): B4248

    PubMed  Google Scholar 

  72. Drucker DJ, Nauck MA. The incretin system: glucagon-like pep tide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006 Nov 11; 368(9548): 1696–705

    Article  CAS  PubMed  Google Scholar 

  73. Hillman M, Eriksson L, Mared L, et al. Reduced levels of active GLP-1 in patients with cystic fibrosis with and without diabetes mellitus. J Cyst Fibros 2012 Mar; 11(2): 144–9

    Article  CAS  PubMed  Google Scholar 

  74. Kuo P, Stevens JE, Russo A, et al. Gastric emptying, incretin hormone secretion, and postprandial glycemia in cystic fibrosis: effects of pancreatic enzyme supplementation. J Clin Endocrinol Metab 2011 May; 96(5): E851–5

    Article  CAS  PubMed  Google Scholar 

  75. Triantafyllou K, Kalantzis C, Papadopoulos AA, et al. Video-capsule endoscopy gastric and small bowel transit time and completeness of the examination in patients with diabetes mellitus. Dig Liver Dis 2007 Jun; 39(6): 575–80

    Article  CAS  PubMed  Google Scholar 

  76. Jung HK, Kim DY, Moon IH, et al. Colonic transit time in diabetic patients: comparison with healthy subjects and the effect of autonomic neuropathy. Yonsei Med J 2003 Apr 30; 44(2): 265–72

    Article  PubMed  Google Scholar 

  77. Wu MJ, Chang CS, Cheng CH, et al. Colonic transit time in long-term dialysis patients. Am J Kidney Dis 2004 Aug; 44(2): 322–7

    Article  PubMed  Google Scholar 

  78. Iida M, Ikeda M, Kishimoto M, et al. Evaluation of gut motility in type II diabetes by the radiopaque marker method. J Gastroenterol Hepatol 2000 Apr; 15(4): 381–5

    Article  CAS  PubMed  Google Scholar 

  79. Werth B, Meyer-Wyss B, Spinas GA, et al. Non-invasive assessment of gastrointestinal motility disorders in diabetic patients with and without cardiovascular signs of autonomic neuropathy. Gut 1992 Sep; 33(9): 1199–203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Scarpello JH, Greaves M, Sladen GE. Small intestinal transit in diabetics. Br Med J 1976 Nov 20; 2(6046): 1225–6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Dooley CP, el Newihi HM, Zeidler A, et al. Abnormalities of the migrating motor complex in diabetics with autonomic neuropathy and diarrhea. Scand J Gastroenterol 1988 Mar; 23(2): 217–23

    Article  CAS  PubMed  Google Scholar 

  82. Oliveira RB, Troncon LE, Meneghelli UG, et al. Gastric accommodation to distension and early gastric emptying in diabetics with neuropathy. Braz J Med Biol Res 1984; 17(1): 49–53

    CAS  PubMed  Google Scholar 

  83. Fraser RJ, Horowitz M, Maddox AF, et al. Hyperglycaemia slows gastric emptying in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1990 Nov; 33(11): 675–80

    Article  CAS  PubMed  Google Scholar 

  84. Jebbink RJ, Samsom M, Bruijs PP, et al. Hyperglycemia induces abnormalities of gastric myoelectrical activity in patients with type I diabetes mellitus. Gastroenterology 1994 Nov; 107(5): 1390–7

    Article  CAS  PubMed  Google Scholar 

  85. Della-Coletta A, Eller M. The bioavailability of tolazamid in diabetic patients and healthy subjects [abstract no. PP 1301]. Pharmacol Res 1988; 5: S174

    Google Scholar 

  86. Adithan C, Danda D, Shashindran CH, et al. Differential effect of type I and type II diabetes mellitus on antipyrine elimination. Methods Find Exp Clin Pharmacol 1989 Dec; 11(12): 755–8

    CAS  PubMed  Google Scholar 

  87. O’Connell ME, Awni WM, Goodman M, et al. Bioavailability and disposition of metoclopramide after single- and multiple-dose administration in diabetic patients with gastroparesis. J Clin Pharmacol 1987 Aug; 27(8): 610–4

    Article  PubMed  Google Scholar 

  88. Wahlin-Boll E, Almer LO, Melander A. Bioavailability, pharmacokinetics and effects of glipizide in type 2 diabetics. Clin Pharmacokinet 1982 Jul–Aug; 7(4): 363–72

    Article  CAS  PubMed  Google Scholar 

  89. Fuccella LM, Tamassia V, Valzelli G. Metabolism and kinetics of the hypoglycemic agent glipizide in man: comparison with glibenclamide. J Clin Pharmacol New Drugs 1973 Feb–Mar; 13(2): 68–75

    Article  CAS  PubMed  Google Scholar 

  90. Stacher G, Lenglinger J, Bergmann H, et al. Gastric emptying: a contributory factor in gastro-oesophageal reflux activity? Gut 2000 Nov; 47(5): 661–6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Maganti K, Onyemere K, Jones MP. Oral erythromycin and symptomatic relief of gastroparesis: a systematic review. Am J Gastroenterol 2003 Feb; 98(2): 259–63

    CAS  PubMed  Google Scholar 

  92. Havelund T, Oster-Jorgensen E, Eshoj O, et al. Effects of cisapride on gastroparesis in patients with insulin-dependent diabetes mellitus: a double-blind controlled trial. Acta Med Scand 1987; 222(4): 339–43

    Article  CAS  PubMed  Google Scholar 

  93. de Caestecker JS, Ewing DJ, Tothill P, et al. Evaluation of oral cisapride and metoclopramide in diabetic autonomic neuropathy: an eight-week double-blind crossover study. Aliment Pharmacol Ther 1989 Feb; 3(1): 69–81

    Article  PubMed  Google Scholar 

  94. Camilleri M, Malagelada JR, Abell TL, et al. Effect of six weeks of treatment with cisapride in gastroparesis and intestinal pseudoobstruction. Gastroenterology 1989 Mar; 96(3): 704–12

    Article  CAS  PubMed  Google Scholar 

  95. Nosadini R, De Kreutzenberg S, Duner E, et al. Porcine and human insulin absorption from subcutaneous tissues in normal and insulin-dependent diabetic subjects: a deconvolution-based approach. J Clin Endocrinol Metab 1988; 67(3): 551–9

    Article  CAS  PubMed  Google Scholar 

  96. Moore EW, Mitchell ML, Chalmers TC. Variability in absorption of insulin-I 131 in normal and diabetic subjects after subcutaneous and intramuscular injection. J Clin Invest 1959 Jul; 38(7): 1222–7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Leinonen H, Matikainen E, Juntunen J. Permeability and morphology of skeletal muscle capillaries in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1982 Mar; 22(3): 158–62

    Article  CAS  PubMed  Google Scholar 

  98. Weinstein L, Meade RH. Absorption and excretion of penicillin injected into the muscles of patients with diabetes mellitus. Nature 1961 Dec 9; 192: 987–8

    Article  CAS  PubMed  Google Scholar 

  99. Hildebrandt P, Sestoft L, Nielsen SL. The absorption of subcutaneously injected short-acting soluble insulin: influence of injection technique and concentration. Diabetes Care 1983 Sep–Oct; 6(5): 459–62

    Article  CAS  PubMed  Google Scholar 

  100. Sestoft L, Volund A, Gammeltoft S, et al. The biological properties of human insulin: subcutaneous absorption, receptor binding and the clinical effect in diabetics assessed by a new statistical method. Acta Med Scand 1982; 212(1–2): 21–8

    CAS  PubMed  Google Scholar 

  101. Kolendorf K, Bojsen J, Nielsen SL. Adipose tissue blood flow and insulin disappearance from subcutaneous tissue. Clin Pharmacol Ther 1979 May; 25 (5 Pt 1): 598–604

    Article  CAS  PubMed  Google Scholar 

  102. Lauritzen T, Binder C, Faber OK. Importance of insulin absorption, subcutaneous blood flow, and residual beta-cell function in insulin therapy. Acta Paediatr Scand Suppl 1980; 283: 81–5

    Article  CAS  PubMed  Google Scholar 

  103. Haggendal E, Steen B, Svanborg A. Blood flow in subcutaneous fat tissue in patients with diabetes mellitus. Acta Med Scand 1970 Jan–Feb; 187(1–2): 49–53

    CAS  PubMed  Google Scholar 

  104. Dimitriadis G, Lambadiari V, Mitrou P, et al. Impaired postprandial blood flow in adipose tissue may be an early marker of insulin resistance in type 2 diabetes. Diabetes Care 2007 Dec; 30(12): 3128–30

    Article  CAS  PubMed  Google Scholar 

  105. Coppack SW, Evans RD, Fisher RM, et al. Adipose tissue metabolism in obesity: lipase action in vivo before and after a mixed meal. Metabolism 1992 Mar; 41(3): 264–72

    Article  CAS  PubMed  Google Scholar 

  106. Blaak EE, van Baak MA, Kemerink GJ, et al. Beta-adrenergic stimulation and abdominal subcutaneous fat blood flow in lean, obese, and reduced-obese subjects. Metabolism 1995 Feb; 44(2): 183–7

    Article  CAS  PubMed  Google Scholar 

  107. Summers LK, Samra JS, Humphreys SM, et al. Subcutaneous abdominal adipose tissue blood flow: variation within and between subjects and relationship to obesity. Clin Sci (Lond) 1996 Dec; 91(6): 679–83

    Article  CAS  Google Scholar 

  108. Jansson PA, Larsson A, Lonnroth PN. Relationship between blood pressure, metabolic variables and blood flow in obese subjects with or without non-insulin-dependent diabetes mellitus. Eur J Clin Invest 1998 Oct; 28(10): 813–8

    Article  CAS  PubMed  Google Scholar 

  109. Karpe F, Fielding BA, Ilic V, et al. Impaired postprandial adipose tissue blood flow response is related to aspects of insulin sensitivity. Diabetes 2002 Aug; 51(8): 2467–73

    Article  CAS  PubMed  Google Scholar 

  110. Regensteiner JG, Popylisen S, Bauer TA, et al. Oral L-arginine and vitamins E and C improve endothelial function in women with type 2 diabetes. Vasc Med 2003; 8(3): 169–75

    Article  PubMed  Google Scholar 

  111. Kingwell BA, Formosa M, Muhlmann M, et al. Type 2 diabetic individuals have impaired leg blood flow responses to exercise: role of endothelium-dependent vasodilation. Diabetes Care 2003 Mar; 26(3): 899–904

    Article  PubMed  Google Scholar 

  112. McVeigh GE, Brennan GM, Johnston GD, et al. Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1992 Aug; 35(8): 771–6

    CAS  PubMed  Google Scholar 

  113. Williams SB, Cusco JA, Roddy MA, et al. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 1996 Mar 1; 27(3): 567–74

    Article  CAS  PubMed  Google Scholar 

  114. Schneider JG, Tilly N, Hierl T, et al. Elevated plasma endothelin-1 levels in diabetes mellitus. Am J Hypertens 2002 Nov; 15(11): 967–72

    Article  CAS  PubMed  Google Scholar 

  115. Marin P, Andersson B, Krotkiewski M, et al. Muscle fiber composition and capillary density in women and men with NIDDM. Diabetes Care 1994 May; 17(5): 382–6

    Article  CAS  PubMed  Google Scholar 

  116. Mathieu-Costello O, Kong A, Ciaraldi TP, et al. Regulation of skeletal muscle morphology in type 2 diabetic subjects by troglitazone and metformin: relationship to glucose disposal. Metabolism 2003 May; 52(5): 540–6

    Article  CAS  PubMed  Google Scholar 

  117. Ritov VB, Menshikova EV, He J, et al. Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. Diabetes 2005 Jan; 54(1): 8–14

    Article  CAS  PubMed  Google Scholar 

  118. Kelley DE, He J, Menshikova EV, et al. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 2002 Oct; 51(10): 2944–50

    Article  CAS  PubMed  Google Scholar 

  119. Yee GC, Evans WE. Reappraisal of guidelines for pharmacokinetic monitoring of aminoglycosides. Pharmacotherapy 1981 Jul–Aug; 1(1): 55–75

    Article  CAS  PubMed  Google Scholar 

  120. Lerner PI, Weinstein L. Abnormalities of absorption of benzylpenicillin G and sulfisoxazole in patients with diabetes mellitus. Am J Med Sci 1964 Jul; 248:37–51

    Article  CAS  PubMed  Google Scholar 

  121. Bonadonna RC, Groop L, Kraemer N, et al. Obesity and insulin resistance in humans: a dose-response study. Metabolism 1990 May; 39(5): 452–9

    Article  CAS  PubMed  Google Scholar 

  122. Rexrode KM, Manson JE, Hennekens CH. Obesity and cardiovascular disease. Curr Opin Cardiol 1996 Sep; 11(5): 490–5

    Article  CAS  PubMed  Google Scholar 

  123. Hanley MJ, Abernethy DR, Greenblatt DJ. Effect of obesity on the pharmacokinetics of drugs in humans. Clin Pharmacokinet 2010; 49(2): 71–87

    Article  CAS  PubMed  Google Scholar 

  124. Benedek IH, Fiske 3rd WD, Griffen WO, et al. Serum alpha 1-acid glycoprotein and the binding of drugs in obesity. Br J Clin Pharmacol 1983 Dec; 16(6): 751–4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Abernethy DR, Greenblatt DJ. Drug disposition in obese humans: an update. Clin Pharmacokinet 1986 May–Jun; 11(3): 199–213

    Article  CAS  PubMed  Google Scholar 

  126. Abernethy DR, Greenblatt DJ, Divoll M, et al. Enhanced glucuronide conjugation of drugs in obesity: studies of lorazepam, oxazepam, and acetaminophen. J Lab Clin Med 1983 Jun; 101(6): 873–80

    CAS  PubMed  Google Scholar 

  127. Abel ED, Litwin SE, Sweeney G. Cardiac remodeling in obesity. Physiol Rev 2008 Apr; 88(2): 389–419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Cohen MP, Ziyadeh FN, Chen S. Amadori-modified glycated serum proteins and accelerated atherosclerosis in diabetes: pathogenic and therapeutic implications. J Lab Clin Med 2006 May; 147(5): 211–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Day JF, Thorpe SR, Baynes JW. Nonenzymatically glucosylated albumin: in vitro preparation and isolation from normal human serum. J Biol Chem 1979 Feb 10; 254(3): 595–7

    CAS  PubMed  Google Scholar 

  130. Adithan C, Danda D, Swaminathan RP, et al. Effect of diabetes mellitus on salivary paracetamol elimination. Clin Exp Pharmacol Physiol 1988 Jun; 15(6): 465–71

    Article  CAS  PubMed  Google Scholar 

  131. Daintith H, Stevenson IH, O’Malley K. Influence of diabetes mellitus on drug metabolism in man. Int J Clin Pharmacol Biopharm 1976 Jan; 13(1): 55–8

    CAS  PubMed  Google Scholar 

  132. Salmela PI, Sotaniemi EA, Pelkonen RO. The evaluation of the drug-metabolizing capacity in patients with diabetes mellitus. Diabetes 1980 Oct; 29(10): 788–94

    Article  CAS  PubMed  Google Scholar 

  133. Murali KV, Adithan C, Shashindran CH, et al. Antipyrine metabolism in patients with diabetes mellitus. Clin Exp Pharmacol Physiol 1983 Jan–Feb; 10(1): 7–13

    Article  CAS  PubMed  Google Scholar 

  134. Pirttiaho HI, Salmela PI, Sotaniemi EA, et al. Drug metabolism in diabetic subjects with fatty livers. Br J Clin Pharmacol 1984 Dec; 18(6): 895–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Narang AP, Dutta DV, Khare AK. Impairment of drug clearance in patients with diabetes mellitus & liver cirrhosis. Indian J Med Res 1987 Mar; 85: 321–5

    CAS  PubMed  Google Scholar 

  136. Zysset T, Wietholtz H. Differential effect of type I and type II diabetes on antipyrine disposition in man. Eur J Clin Pharmacol 1988; 34(4): 369–75

    Article  CAS  PubMed  Google Scholar 

  137. Ruiz-Cabello F, Erill S. Abnormal serum protein binding of acidic drugs in diabetes mellitus. Clin Pharmacol Ther 1984 Nov; 36(5): 691–5

    Article  CAS  PubMed  Google Scholar 

  138. Worner W, Preissner A, Rietbrock N. Drug-protein binding kinetics in patients with type I diabetes. Eur J Clin Pharmacol 1992; 43(1): 97–100

    Article  CAS  PubMed  Google Scholar 

  139. Kearns GL, Kemp SF, Turley CP, et al. Protein binding of phenytoin and lidocaine in pediatric patients with type I diabetes mellitus. Dev Pharmacol Ther 1988; 11(1): 14–23

    CAS  PubMed  Google Scholar 

  140. Kemp SF, Kearns GL, Turley CP. Alteration of phenytoin binding by glycosylation of albumin in IDDM. Diabetes 1987 Apr; 36(4): 505–9

    Article  CAS  PubMed  Google Scholar 

  141. Trovik TS, Jaeger R, Jorde R, et al. Plasma protein binding of catecholamines, prazosin and propranolol in diabetes mellitus. Eur J Clin Pharmacol 1992; 43(3): 265–8

    Article  CAS  PubMed  Google Scholar 

  142. Trovik TS, Jaeger R, Jorde R, et al. Reduced sensitivity to beta-adrenoceptor stimulation and blockade in insulin dependent diabetic patients with hypoglycaemia unawareness. Br J Clin Pharmacol 1994 Nov; 38(5): 427–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Reidenberg MM, Drayer DE. Alteration of drug-protein binding in renal disease. Clin Pharmacokinet 1984 Jan; 9 Suppl. 1: 18–26

    Article  PubMed  Google Scholar 

  144. Keller F, Maiga M, Neumayer HH, et al. Pharmacokinetic effects of altered plasma protein binding of drugs in renal disease. Eur J Drug Metab Pharmacokinet 1984 Jul–Sep; 9(3): 275–82

    Article  CAS  PubMed  Google Scholar 

  145. Gatti G, Crema F, Attardo-Parrinello G, et al. Serum protein binding of phenytoin and valproic acid in insulin-dependent diabetes mellitus. Ther Drug Monit 1987 Dec; 9(4): 389–91

    Article  CAS  PubMed  Google Scholar 

  146. McNamara PJ, Blouin RA, Brazzell RK. The protein binding of phenytoin, propranolol, diazepam, and AL01576 (an aldose reductase inhibitor) in human and rat diabetic serum. Pharm Res 1988 May; 5(5): 261–5

    Article  CAS  PubMed  Google Scholar 

  147. Zini R, Riant P, Barre J, et al. Disease-induced variations in plasma protein levels. Implications for drug dosage regimens (part II). Clin Pharmacokinet 1990 Sep; 19(3): 218–29

    Article  CAS  PubMed  Google Scholar 

  148. Chase HP, Glasgow AM. Juvenile diabetes mellitus and serum lipids and lipoprotein levels. Am J Dis Child 1976 Oct; 130(10): 1113–7

    CAS  PubMed  Google Scholar 

  149. Fraze E, Donner CC, Swislocki AL, et al. Ambient plasma free fatty acid concentrations in noninsulin-dependent diabetes mellitus: evidence for insulin resistance. J Clin Endocrinol Metab 1985 Nov; 61(5): 807–11

    Article  CAS  PubMed  Google Scholar 

  150. Grainger-Rousseau T, McElnay J, Collier P. The influence of disease on plasma protein binding of drugs. Int J Pharmacol 1989; 54: 1–13

    Article  CAS  Google Scholar 

  151. O’Byrne S, Barry MG, Collins WC, et al. Plasma protein binding of lidocaine and warfarin in insulin-dependent and non-insulin-dependent diabetes mellitus. Clin Pharmacokinet 1993 Feb; 24(2): 183–6

    Article  PubMed  Google Scholar 

  152. Stafford WL. Abnormality in the binding of an organic anion by diabetic serum. Lancet 1962 Feb 3; 1(7223): 243–5

    Article  CAS  PubMed  Google Scholar 

  153. Saadeh S. Nonalcoholic Fatty liver disease and obesity. Nutr Clin Pract 2007 Feb; 22(1): 1–10

    Article  PubMed  Google Scholar 

  154. Ijaz S, Yang W, Winslet MC, et al. Impairment of hepatic microcirculation in fatty liver. Microcirculation 2003 Dec; 10(6): 447–56

    Article  CAS  PubMed  Google Scholar 

  155. Kotlyar M, Carson SW. Effects of obesity on the cytochrome P450 enzyme system. Int J Clin Pharmacol Ther 1999 Jan; 37(1): 8–19

    CAS  PubMed  Google Scholar 

  156. Abernethy DR, Greenblatt DJ. Pharmacokinetics of drugs in obesity. Clin Pharmacokinet 1982 Mar–Apr; 7(2): 108–24

    Article  CAS  PubMed  Google Scholar 

  157. Petrides AS, Vogt C, Schulze-Berge D, et al. Pathogenesis of glucose intolerance and diabetes mellitus in cirrhosis. Hepatology 1994 Mar; 19(3): 616–27

    Article  CAS  PubMed  Google Scholar 

  158. Katbamma B, Petrelli M, McCullough A. The liver in diabetes mellitus and hyperlipidemia. In: Gitlin N, editor. The liver and the systemic disease. New York: Churchill Livingstone, 1997: 73–113

    Google Scholar 

  159. Wang T, Fontenot RD, Soni MG, et al. Enhanced hepatotoxicity and toxic outcome of thioacetamide in streptozotocin-induced diabetic rats. Toxicol Appl Pharmacol 2000 Jul 15; 166(2): 92–100

    Article  CAS  PubMed  Google Scholar 

  160. Watkins 3rd JB, Sherman SE. Long-term diabetes alters the hepatobiliary clearance of acetaminophen, bilirubin and digoxin. J Pharmacol Exp Ther 1992 Mar; 260(3): 1337–43

    CAS  PubMed  Google Scholar 

  161. Shankar K, Vaidya VS, Apte UM, et al. Type 1 diabetic mice are protected from acetaminophen hepatotoxicity. Toxicol Sci 2003 Jun; 73(2): 220–34

    Article  CAS  PubMed  Google Scholar 

  162. Lee JH, Yang SH, Oh JM, et al. Pharmacokinetics of drugs in rats with diabetes mellitus induced by alloxan or streptozotocin: comparison with those in patients with type I diabetes mellitus. J Pharm Pharmacol 2010; 62(1): 1–23

    Article  CAS  PubMed  Google Scholar 

  163. Cheng PY, Morgan ET. Hepatic cytochrome P450 regulation in disease states. Curr Drug Metab 2001 Jun; 2(2): 165–83

    Article  CAS  PubMed  Google Scholar 

  164. Sotaniemi EA, Pelkonen O, Arranto AJ, et al. Diabetes and elimination of antipyrine in man: an analysis of 298 patients classified by type of diabetes, age, sex, duration of disease and liver involvement. Pharmacol Toxicol 2002 Mar; 90(3): 155–60

    Article  CAS  PubMed  Google Scholar 

  165. Lucas D, Farez C, Bardou LG, et al. Cytochrome P450 2E1 activity in diabetic and obese patients as assessed by chlorzoxazone hydroxylation. Fundam Clin Pharmacol 1998; 12(5): 553–8

    Article  CAS  PubMed  Google Scholar 

  166. Wang Z, Hall SD, Maya JF, et al. Diabetes mellitus increases the in vivo activity of cytochrome P450 2E1 in humans. Br J Clin Pharmacol 2003 Jan; 55(1): 77–85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Hannon-Fletcher MP, O’Kane MJ, Moles KW, et al. Lymphocyte cytochrome P450-CYP2E1 expression in human IDDM subjects. Food Chem Toxicol 2001 Feb; 39(2): 125–32

    Article  CAS  PubMed  Google Scholar 

  168. Haufroid V, Ligocka D, Buysschaert M, et al. Cytochrome P4502E1 (CYP2E1) expression in peripheral blood lymphocytes: evaluation in hepatitis C and diabetes. Eur J Clin Pharmacol 2003 May; 59(1): 29–33

    Article  CAS  PubMed  Google Scholar 

  169. Song BJ, Veech RL, Saenger P. Cytochrome P450IIE1 is elevated in lymphocytes from poorly controlled insulin-dependent diabetics. J Clin Endocrinol Metab 1990 Oct; 71(4): 1036–40

    Article  CAS  PubMed  Google Scholar 

  170. Pucci L, Chirulli V, Marini S, et al. Expression and activity of CYP2E1 in circulating lymphocytes are not altered in diabetic individuals. Pharmacol Res 2005 Jun; 51(6): 561–5

    Article  CAS  PubMed  Google Scholar 

  171. Adithan C, Sriram G, Swaminathan RP, et al. Effect of type II diabetes mellitus on theophylline elimination. Int J Clin Pharmacol Ther Toxicol 1989 May; 27(5): 258–60

    CAS  PubMed  Google Scholar 

  172. Zysset T, Wietholtz H. Pharmacokinetics of caffeine in patients with decompensated type I and type II diabetes mellitus. Eur J Clin Pharmacol 1991; 41(5): 449–52

    Article  CAS  PubMed  Google Scholar 

  173. Matzke GR, Frye RF, Early JJ, et al. Evaluation of the influence of diabetes mellitus on antipyrine metabolism and CYP1A2 and CYP2D6 activity. Pharmacotherapy 2000 Feb; 20(2): 182–90

    Article  CAS  PubMed  Google Scholar 

  174. Korrapati MR, Vestal RE, Loi CM. Theophylline metabolism in healthy nonsmokers and in patients with insulin-dependent diabetes mellitus. Clin Pharmacol Ther 1995 Apr; 57(4): 413–8

    Article  CAS  PubMed  Google Scholar 

  175. Ueda H, Sakurai T, Ota M, et al. Disappearance rate of tolbutamide in normal subjects and in diabetes mellitus, liver cirrhosis, and renal disease. Diabetes 1963 Sep–Oct; 12: 414–9

    Article  CAS  PubMed  Google Scholar 

  176. Dyer JR, Davis TM, Giele C, et al. The pharmacokinetics and pharmacodynamics of quinine in the diabetic and non-diabetic elderly. Br J Clin Pharmacol 1994 Sep; 38(3): 205–12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Dostalek M, Court MH, Yan B, et al. Significantly reduced cytochrome P450 3A4 expression and activity in liver from humans with diabetes mellitus. Br J Pharmacol 2011 Jul; 163(5): 937–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Marques MP, Coelho EB, Dos Santos NA, et al. Dynamic and kinetic disposition of nisoldipine enantiomers in hypertensive patients presenting with type-2 diabetes mellitus. Eur J Clin Pharmacol 2002 Dec; 58(9): 607–14

    Article  CAS  PubMed  Google Scholar 

  179. Moises EC, Duarte Lde B, Cavalli Rde C, et al. Pharmacokinetics of lidocaine and its metabolite in peridural anesthesia administered to pregnant women with gestational diabetes mellitus. Eur J Clin Pharmacol 2008 Dec; 64(12): 1189–96

    Article  CAS  PubMed  Google Scholar 

  180. McRobie DJ, Glover DD, Tracy TS. Effects of gestational and overt diabetes on human placental cytochromes P450 and glutathione S-transferase. Drug Metab Dispos 1998 Apr; 26(4): 367–71

    CAS  PubMed  Google Scholar 

  181. McRobie DJ, Korzekwa KR, Glover DD, et al. The effects of diabetes on placental aromatase activity. J Steroid Biochem Mol Biol 1997 Sep–Oct; 63(1–3): 147–53

    Article  CAS  PubMed  Google Scholar 

  182. Juan D, Molitch ME, Johnson MK, et al. Unaltered drug metabolizing enzyme systems in type II diabetes mellitus before and during glyburide therapy. J Clin Pharmacol 1990 Oct; 30(10): 943–7

    Article  CAS  PubMed  Google Scholar 

  183. West IC. Radicals and oxidative stress in diabetes. Diabet Med 2000 Mar; 17(3): 171–80

    Article  CAS  PubMed  Google Scholar 

  184. Atalay M, Laaksonen DE, Niskanen L, et al. Altered antioxidant enzyme defences in insulin-dependent diabetic men with increased resting and exercise-induced oxidative stress. Acta Physiol Scand 1997 Oct; 161(2): 195–201

    Article  CAS  PubMed  Google Scholar 

  185. Dincer Y, Alademir Z, Ilkova H, et al. Susceptibility of glutatione and glutathione-related antioxidant activity to hydrogen peroxide in patients with type 2 diabetes: effect of glycemic control. Clin Biochem 2002 Jun; 35(4): 297–301

    Article  CAS  PubMed  Google Scholar 

  186. Graber R, Farine JC, Fumagalli I, et al. Apoptosis and oxidative status in peripheral blood mononuclear cells of diabetic patients. Apoptosis 1999 Aug; 4(4): 263–70

    Article  CAS  PubMed  Google Scholar 

  187. Sailaja YR, Baskar R, Saralakumari D. The antioxidant status during maturation of reticulocytes to erythrocytes in type 2 diabetics. Free Radic Biol Med 2003 Jul 15; 35(2): 133–9

    Article  CAS  PubMed  Google Scholar 

  188. Albrecht C, Simon-Vermot I, Elliott JI, et al. Leukocyte ABCA1 gene expression is associated with fasting glucose concentration in normoglycemic men. Metabolism 2004 Jan; 53(1): 17–21

    Article  CAS  PubMed  Google Scholar 

  189. Zhou H, Tan KC, Shiu SW, et al. Determinants of leukocyte adenosine triphosphate-binding cassette transporter G1 gene expression in type 2 diabetes mellitus. Metabolism 2008 Aug; 57(8): 1135–40

    Article  CAS  PubMed  Google Scholar 

  190. Mauldin JP, Nagelin MH, Wojcik AJ, et al. Reduced expression of ATP-binding cassette transporter G1 increases cholesterol accumulation in macrophages of patients with type 2 diabetes mellitus. Circulation 2008 May 27; 117(21): 2785–92

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Blouin RA, Warren GW. Pharmacokinetic considerations in obesity. J Pharm Sci 1999 Jan; 88(1): 1–7

    Article  CAS  PubMed  Google Scholar 

  192. Suzuki Y, Arakawa M. The treatment of the uraemic diabetic. Are we doing enough? A view from Japan. Fumitake Gejyo and Collaborate Study Group. Nephrol Dial Transplant 1995; 10 Suppl. 7: 47–55

    Article  PubMed  Google Scholar 

  193. Raine AE. The rising tide of diabetic nephropathy: the warning before the flood? Nephrol Dial Transplant 1995; 10(4): 460–1

    Article  CAS  PubMed  Google Scholar 

  194. Andersen AR, Christiansen JS, Andersen JK, et al. Diabetic nephropathy in type 1 (insulin-dependent) diabetes: an epidemiological study. Diabetologia 1983 Dec; 25(6): 496–501

    Article  CAS  PubMed  Google Scholar 

  195. Sasso FC, De Nicola L, Carbonara O, et al. Cardiovascular risk factors and disease management in type 2 diabetic patients with diabetic nephropathy. Diabetes Care 2006 Mar; 29(3): 498–503

    Article  PubMed  Google Scholar 

  196. Hasslacher C, Kempe HP, Bostedt-Kiesel A. ACE inhibitors and diabetic nephropathy: clinical and experimental findings. Clin Investig 1993; 71 (5 Suppl.): S20–4

    CAS  PubMed  Google Scholar 

  197. Ebihara I, Nakamura T, Shimada N, et al. Increased plasma metalloproteinase-9 concentrations precede development of microalbuminuria in non-insulin-dependent diabetes mellitus. Am J Kidney Dis 1998 Oct; 32(4): 544–50

    Article  CAS  PubMed  Google Scholar 

  198. Ravid M, Lang R, Rachmani R, et al. Long-term renoprotective effect of angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus: a 7-year follow-up study. Arch Intern Med 1996 Feb 12; 156(3): 286–9

    Article  CAS  PubMed  Google Scholar 

  199. Ahmad J, Siddiqui MA, Ahmad H. Effective postponement of diabetic nephropathy with enalapril in normotensive type 2 diabetic patients with microalbuminuria. Diabetes Care 1997 Oct; 20(10): 1576–81

    Article  CAS  PubMed  Google Scholar 

  200. Gill GV, Hardy KJ, Patrick AW, et al. Random blood glucose estimation in type 2 diabetes: does it reflect overall glycaemic control? Diabet Med 1994 Aug–Sep; 11(7): 705–8

    Article  CAS  PubMed  Google Scholar 

  201. Meeme A, Kasozi H. Effect of glycaemic control on glomerular filtration rate in diabetes mellitus patients. Afr Health Sci 2009 Aug 1; 9 Suppl. 1: S23–6

    PubMed  PubMed Central  Google Scholar 

  202. Maurer AC. The therapy of diabetes. Am Sci 1979 Jul–Aug; 67(4): 422–31

    CAS  PubMed  Google Scholar 

  203. Madacsy L, Bokor M, Matusovits L. Penicillin clearance in diabetic children. Acta Paediatr Acad Sci Hung 1975; 16(2): 139–42

    CAS  PubMed  Google Scholar 

  204. Garcia G, de Vidal EL, Trujillo H. Serum levels and urinary concentrations of kanamicin, bekanamicin and amikacin (BB-K8) in diabetic children and a control group. J Int Med Res 1977; 5(5): 322–9

    Article  CAS  PubMed  Google Scholar 

  205. Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004 Dec 1; 292(21): 2585–90

    Article  CAS  PubMed  Google Scholar 

  206. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004 Aug 21–27; 364(9435): 685–96

    Article  CAS  PubMed  Google Scholar 

  207. Skottheim IB, Gedde-Dahl A, Hejazifar S, et al. Statin induced myotoxicity: the lactone forms are more potent than the acid forms in human skeletal muscle cells in vitro. Eur J Pharm Sci 2008 Apr 23; 33(4–5): 317–25

    Article  CAS  PubMed  Google Scholar 

  208. Berlin I, Grimaldi A, Bosquet F, et al. Decreased beta-adrenergic sensitivity in insulin-dependent diabetic subjects. J Clin Endocrinol Metab 1986 Jul; 63(1): 262–5

    Article  CAS  PubMed  Google Scholar 

  209. Lloyd-Mostyn RH, Watkins PJ. Defective innervation of heart in diabetic autonomic neuropathy. Br Med J 1975 Jul 5; 3(5974): 15–7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Berlin I, Grimaldi A, Landault C, et al. Lack of hypoglycemic symptoms and decreased beta-adrenergic sensitivity in insulin-dependent diabetic patients. J Clin Endocrinol Metab 1988 Feb; 66(2): 273–8

    Article  CAS  PubMed  Google Scholar 

  211. Berlin I, Grimaldi A, Payan C, et al. Hypoglycemic symptoms and decreased beta-adrenergic sensitivity in insulin-dependent diabetic patients. Diabetes Care 1987 Nov–Dec; 10(6): 742–7

    Article  CAS  PubMed  Google Scholar 

  212. Lynch C, Exton J. Alterations in G-protein-mediated cell signaling in diabetes mellitus. In: Milligan G, Wakelam M, editors. G-proteins: signal transduction and disease. London: Academic Press Limited, 1992: 87–108

    Google Scholar 

  213. Terada M, Yasuda H, Kashawagi A, et al. Sympathetic nerve dysfunction and increased heart rate response to epinephrine in diabetic patients. Amsterdam: Elsevier Science Publishers, 1987

    Google Scholar 

  214. Packer M, Lee WH, Medina N, et al. Influence of diabetes mellitus on changes in left ventricular performance and renal function produced by converting enzyme inhibition in patients with severe chronic heart failure. Am J Med 1987 Jun; 82(6): 1119–26

    Article  CAS  PubMed  Google Scholar 

  215. Self TH, Hood J, Miller ST. Diabetes mellitus and the hypoprothrombinemic response to warfarin [letter]. JAMA 1978 May 26; 239(21): 2239

    Article  CAS  PubMed  Google Scholar 

  216. Lansang MC, Ma L, Schold JD, et al. The relationship between diabetes and infectious hospitalizations in renal transplant recipients. Diabetes Care 2006 Jul; 29(7): 1659–60

    Article  PubMed  Google Scholar 

  217. First MR. Posttransplant diabetes mellitus [letter]. Transplantation 2003 May 27; 75(10): 1769

    Article  PubMed  Google Scholar 

  218. Kasiske BL, Snyder JJ, Gilbertson D, et al. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 2003 Feb; 3(2): 178–85

    Article  PubMed  Google Scholar 

  219. Ye X, Kuo HT, Sampaio MS, et al. Risk factors for development of new-onset diabetes mellitus after transplant in adult lung transplant recipients. Clin Transplant 2011; 25(6): 885–91

    Article  PubMed  Google Scholar 

  220. Mendonza AE, Gohh RY, Akhlaghi F. Blood and plasma pharmacokinetics of ciclosporin in diabetic kidney transplant recipients. Clin Pharmacokinet 2008; 47(11): 733–42

    Article  CAS  PubMed  Google Scholar 

  221. Akhlaghi F, Dostalek M, Falck P, et al. The concentration of cyclosporine metabolites is significantly lower in kidney transplant recipients with diabetes mellitus. Ther Drug Monit 2012; 34(1): 38–45

    Article  CAS  PubMed  Google Scholar 

  222. Mendonza AE, Zahir H, Gohh RY, et al. Tacrolimus in diabetic kidney transplant recipients: pharmacokinetics and application of a limited sampling strategy. Ther Drug Monit 2007 Aug; 29(4): 391–8

    Article  CAS  PubMed  Google Scholar 

  223. van Duijnhoven E, Christiaans M, Undre N, et al. The effect of breakfast on the oral bioavailability of tacrolimus in diabetic and nondiabetic patients before transplantation. Transplant Proc 1998 Jun; 30(4): 1268–70

    Article  PubMed  Google Scholar 

  224. Akhlaghi F, Patel CG, Zuniga XP, et al. Pharmacokinetics of mycophenolic acid and metabolites in diabetic kidney transplant recipients. Ther Drug Monit 2006 Feb; 28(1): 95–101

    Article  CAS  PubMed  Google Scholar 

  225. van Hest RM, Mathot RA, Vulto AG, et al. Mycophenolic acid in diabetic renal transplant recipients: pharmacokinetics and application of a limited sampling strategy. Ther Drug Monit 2004 Dec; 26(6): 620–5

    Article  PubMed  Google Scholar 

  226. Pescovitz MD, Guasch A, Gaston R, et al. Equivalent pharmacokinetics of mycophenolate mofetil in African-American and Caucasian male and female stable renal allograft recipients. Am J Transplant 2003 Dec; 3(12): 1581–6

    Article  CAS  PubMed  Google Scholar 

  227. Akhlaghi F, Dostalek M, Mendonza AE, et al. Reduced levels of biomarkers of immunosuppressive activity in diabetic kidney transplant recipients [poster no. P204]. International Association of Therapeutic Drug Monitoring and Clinical Toxicology; 2011 Oct 2–6; Stuttgart, Germany

    Google Scholar 

  228. Akhlaghi F, Chitnis SD, Ionita I, et al. Impact of diabetes mellitus on metabolism of immunosuppressive agents: cyclosporin, tacrolimus and prednisone [poster no. P201]. International Association of Therapeutic Drug Monitoring and Clinical Toxicology; 2011 Oct 2–6; Stuttgart, Germany

    Google Scholar 

  229. Bertoni AG, Saydah S, Brancati FL. Diabetes and the risk of infection-related mortality in the U.S. Diabetes Care 2001 Jun; 24(6): 1044–9

    Article  CAS  PubMed  Google Scholar 

  230. Alba-Loureiro TC, Munhoz CD, Martins JO, et al. Neutrophil function and metabolism in individuals with diabetes mellitus. Braz J Med Biol Res 2007 Aug; 40(8): 1037–44

    Article  CAS  PubMed  Google Scholar 

  231. Jolin T, Tarin MJ, Garcia MD. Induction of goitre by PTU or KCIO4 in male and female rats: effect of gonadectomy. Acta Endocrinol (Copenh) 1973 Sep; 74(1): 88–104

    CAS  Google Scholar 

  232. Garcia-Leme J, Bohm GM, Migliorini RH, et al. Possible participation of insulin in the control of vascular permeability. Eur J Pharmacol 1974 Dec; 29(2): 298–306

    Article  CAS  PubMed  Google Scholar 

  233. Llorach MA, Bohm GM, Leme JG. Decreased vascular reactions to permeability factors in experimental diabetes. Br J Exp Pathol 1976 Dec; 57(6): 747–54

    CAS  PubMed  PubMed Central  Google Scholar 

  234. Fortes ZB, Garcia Leme J, Scivoletto R. Vascular reactivity in diabetes mellitus: role of the endothelial cell. Br J Pharmacol 1983 Jul; 79(3): 771–81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Fortes ZB, Garcia Leme J, Scivoletto R. Vascular reactivity in diabetes mellitus: possible role of insulin on the endothelial cell. Br J Pharmacol 1984 Nov; 83(3): 635–43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Cavalher-Machado SC, de Lima WT, Damazo AS, et al. Down-regulation of mast cell activation and airway reactivity in diabetic rats: role of insulin. Eur Respir J 2004 Oct; 24(4): 552–8

    Article  CAS  PubMed  Google Scholar 

  237. Sannomiya P, Pereira MA, Garcia-Leme J. Inhibition of leukocyte chemotaxis by serum factor in diabetes mellitus: selective depression of cell responses mediated by complement-derived chemoattractants. Agents Actions 1990 Jun; 30(3–4): 369–76

    Article  CAS  PubMed  Google Scholar 

  238. Sannomiya P, Oliveira MA, Fortes ZB. Aminoguanidine and the prevention of leukocyte dysfunction in diabetes mellitus: a direct vital microscopic study. Br J Pharmacol 1997 Nov; 122(5): 894–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Fortes ZB, Farsky SP, Oliveira MA, et al. Direct vital microscopic study of defective leukocyte-endothelial interaction in diabetes mellitus. Diabetes 1991 Oct; 40(10): 1267–73

    Article  CAS  PubMed  Google Scholar 

  240. Cruz JW, Oliveira MA, Hohman TC, et al. Influence of tolrestat on the defective leukocyte-endothelial interaction in experimental diabetes. Eur J Pharmacol 2000 Mar 10; 391(1–2): 163–74

    Article  CAS  PubMed  Google Scholar 

  241. Zanardo RC, Cruz JW, Martinez LL, et al. Probucol restores the defective leukocyte-endothelial interaction in experimental diabetes. Eur J Pharmacol 2003 Oct 8; 478(2–3): 211–9

    Article  CAS  PubMed  Google Scholar 

  242. Anjos-Valotta EA, Martins JO, Oliveira MA, et al. Inhibition of tumor necrosis factor-alpha-induced intercellular adhesion molecule-1 expression in diabetic rats: role of insulin. Inflamm Res 2006 Jan; 55(1): 16–22

    Article  CAS  PubMed  Google Scholar 

  243. Moriguchi P, Sannomiya P, Lara PF, et al. Lymphatic system changes in diabetes mellitus: role of insulin and hyperglycemia. Diabetes Metab Res Rev 2005; 21(2): 150–7

    Article  CAS  PubMed  Google Scholar 

  244. Boichot E, Sannomiya P, Escofier N, et al. Endotoxin-induced acute lung injury in rats: role of insulin. Pulm Pharmacol Ther 1999; 12(5): 285–90

    Article  CAS  PubMed  Google Scholar 

  245. Shaw LM, Figurski M, Milone MC, et al. Therapeutic drug monitoring of mycophenolic acid. Clin J Am Soc Nephrol 2007 Sep; 2(5): 1062–72

    Article  CAS  PubMed  Google Scholar 

  246. Patel CG, Richman K, Yang D, et al. Effect of diabetes mellitus on mycophenolate sodium pharmacokinetics and inosine monophosphate dehydrogenase activity in stable kidney transplant recipients. Ther Drug Monit 2007 Dec; 29(6): 735–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Jain J, Almquist SJ, Ford PJ, et al. Regulation of inosine monophosphate dehydrogenase type I and type II isoforms in human lymphocytes. Biochem Pharmacol 2004 Feb 15; 67(4): 767–76

    Article  CAS  PubMed  Google Scholar 

  248. Fulton B, Markham A. Mycophenolate mofetil: a review of its pharmaco-dynamic and pharmacokinetic properties and clinical efficacy in renal transplantation. Drugs 1996 Feb; 51(2): 278–98

    Article  CAS  PubMed  Google Scholar 

  249. Abbott KC, Hypolite I, Poropatich RK, et al. Hospitalizations for fungal infections after renal transplantation in the United States. Transpl Infect Dis 2001 Dec; 3(4): 203–11

    Article  CAS  PubMed  Google Scholar 

  250. Dharnidharka VR, Agodoa LY, Abbott KC. Risk factors for hospitalization for bacterial or viral infection in renal transplant recipients: an analysis of USRDS data. Am J Transplant 2007 Mar; 7(3): 653–61

    Article  CAS  PubMed  Google Scholar 

  251. Redman DR, Prescott LF. Failure of induction of liver microsomal enzymes by tolbutamide in maturity-onset diabetics. Diabetes 1973 Mar; 22(3): 210–1

    Article  CAS  PubMed  Google Scholar 

  252. Sambol NC, Chiang J, O’Conner M, et al. Pharmacokinetics and pharmaco-dynamics of metformin in healthy subjects and patients with noninsulin-dependent diabetes mellitus. J Clin Pharmacol 1996 Nov; 36(11): 1012–21

    Article  CAS  PubMed  Google Scholar 

  253. Plosker GL, Figgitt DP. Repaglinide: a pharmacoeconomic review of its use in type 2 diabetes mellitus. Pharmacoeconomics 2004; 22(6): 389–411

    Article  PubMed  Google Scholar 

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No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

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Correspondence to Martina Puzanovova.

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Dostalek, M., Akhlaghi, F. & Puzanovova, M. Effect of Diabetes Mellitus on Pharmacokinetic and Pharmacodynamic Properties of Drugs. Clin Pharmacokinet 51, 481–499 (2012). https://doi.org/10.1007/BF03261926

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