Summary
This paper reviews the effects of renal insufficiency on the pharmacokinetics of oral antidiabetic drugs. Of the 3 groups of drugs currently available for the treatment of non-insulin-dependent diabetes mellitus (NIDDM), the sulphonylureas and metformin are, in general, well-tolerated and generally safe. In patients with chronic renal insufficiency, however, care must be exercised in the use of many of these drugs, as accumulation, either of the active drug or of active metabolites, can lead to serious adverse effects such as hypoglycaemia or, with metformin, lactic acidosis.
The sulphonylurea drugs, to a greater or lesser degree, are metabolised in the liver to a variety of active or inactive compounds which, in general, are excreted by the kidneys. In addition, varying amounts of parent compound may depend on renal elimination. As a result, sulphonylurea drugs such as tolazamide, acetohexamide, chlorpropamide and glibenclamide (glyburide) are more likely to cause significant hypoglycaemia, as the metabolism of these drugs, compared with other commonly prescribed sulphonylureas, can lead to the accumulation of either the parent drug or the active metabolite in the presence of renal insufficiency. Tolbutamide, glipizide, gliclazide and gliquidone are much less likely to cause hypoglycaemia as their metabolites are either inactive or have minimal hypoglycaemic potency.
Metformin is dependent on renal excretion and is not significantly metabolised. As a result, caution is required when treating patients with renal insufficiency where metformin accumulation can occur, with the danger of lactic acidosis. Although the correlation between creatinine clearance (CLcr) and total oral clearance of drug is weaker than the correlation between CLcr and renal clearance (CLr) of metformin, it is clear that renal insufficiency is associated with most cases of metformin-induced lactic acidosis. For this reason, clinicians in general would regard a raised plasma creatinine as a contraindication to metformin treatment.
Acarbose, an α-glucosidase inhibitor, and a relatively new agent for treating NIDDM, is likely to be safe in patients with impaired renal function, as the drug is not significantly absorbed from the gut, but data on this subject are lacking.
Similar content being viewed by others
References
Grodsky GM, Epstein GH, Fanska R, et al. Pancreatic action of the sulphonylureas. Fed Proc 1977; 36: 2714–9
Henquin J-C. The fiftieth anniversary of hypoglycaemic sulphonamides: how did the mother compound work? Diabetologia 1977; 35: 907–12
Jackson JE, Bressler R. Clinical pharmacology of sulphonylurea hypoglycaemic agents. Drugs 1981; 22: 211–45,295-320
Ferner RE, Chaplin S. The relationship between the pharmacokinetics and pharmacodynamics of oral hypoglycaemic drugs. Clin Pharmacokinet 1987; 12: 379–401
Gerich JE. Oral hypoglycaemic agents. N Engl J Med 1989; 321: 1231–45
Alexander WD, Hayes TM. Metformin and sulphonylureas: a comparison of their effect on lactate levels in diabetics with and without complications. Res Clin Forum 1979; 1: 65–8
Cavallo-Perin P, Aluffi E, Estivi P, et al. The hyperlactatemic effect of biguanides: a comparison between phenformin and metformin during a six month treatment. Med Pharmacol Sci 1989; 11: 45–9
Hermann LS. Metformin: a review of its pharmacological properties and therapeutic use. Diabete Metab 1979; 5: 233–45
Bailey CJ. Biguanides and NIDDM. Diabetes Care 1992; 15: 755–72
Puls W, Keup U, Krause HP, et al. Glucosidase inhibition: a new approach to the treatment of diabetes, obesity and hyperlipoproteinemia. Naturwissenschaften 1977; 64: 536–7
Truscheit E, Hillebrand I, Junge B, et al. Microbial glucosidase inhibitors: chemistry, biochemistry and therapeutic potential. Prog Clin Biochem Med 1988; 7: 17–99
Schmidt DD, Frommer W, Junge B, et al. Glucosidase inhibitors. New complex oligosaccharides of microbial origin. Naturwissenschaften 1977; 64: 535–6
Smith DL, Vecchio TJ, Forist AA. Metabolism of antidiabetic sulphonyl-ureas in man. I. Biological half-lives of the p-acetylbenzenesulphonylureas U-18536 and acetohexamide and their metabolites. Metabolism 1965; 14: 229–40
Galloway JA, McMahon RE, Culp HW, et al. Metabolism, blood levels and rate of excretion of acetohexamide in human subjects. Diabetes 1967; 16: 118–27
Cohen BD, Galloway JA, McMahon RE, et al. Carbohydrate metabolism in uraemia: blood glucose response to sulphonylurea. Am J Med Sci 1967; 254: 608–18
Alexander RW. Prolonged hypoglycaemia following acetohexamide administration. Report of two cases with impaired renal function. Diabetes 1966; 15: 362–4
Scott J, Poffenbarger PL. Pharmacokinetics of tolbutamide metabolism in humans. Diabetes 1979; 28: 41–51
Thomas RC, Ikeda GJ. The metabolic fate of tolbutamide in man and in the rat. J Med Chem 1966; 9: 507–10
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; 12: 414–9
Brotherton PM, Grievson P, McMartin C. A study of the metabolic rate of chlorpropamide in man. Clin Pharmacol Ther 1969; 10: 505–14
Taylor JA. Pharmacokinetics and biotransformation of chlorpropamide in man. Clin Pharmacol Ther 1972; 13: 710–8
Seltzer HS. Drug induced hypoglycaemia, a review based on 473 cases. Diabetes 1972; 21: 955–66
Agarwal RC, Kumar D, Miller LV. Chlorpropamide-induced hypo-glycaemia. Diabetes 1970; 19 Suppl.: 376
Petitpierre B, Perrin L, Reidhardt M, et al. Behaviour of chlorpropamide in renal insufficiency and under the effect of associated drug therapy. Int J Clin Pharmacol 1972; 6: 120–4
Thomas RC, Duchamp DJ, Rudy RW, et al. Metabolic fate of tolazamide in man and in the rat. J Med Chem 1978; 21: 725–32
Rull JA, Lennhoff M. Prolonged and recurrent tolazamideinduced hypo glycaemia: report of a case. Diabetes 1967; 16: 352–3
Balant L, Fabre JM, Loutan L, et al. Does 4-trans-hydroxyglibenclamide show hypoglycaemic activity? Arzneimittelforschung 1979; 29: 162–3
Fabre J, Balant L, Loutan L, et al. Hypoglycaemic activity of the main metabolite of glibenclamide: influence of renal insufficiency [abstract]. Kidney Int 1978; 13: 435
Pearson JG, Antal EJ, Raehl CC, et al. Pharmacokinetic disposition of 14C-glyburide in patients with varying renal function. Clin Pharmacol Ther 1986; 39: 318–24
Asplund K, Wilholm BE, Lithner F. Glibenclamide-associated hypoglycaemia: a report on 57 cases. Diabetologia 1983; 24: 412–7
Berger W. 88 Schwere hypoglykamiezwischenfalle unter der Behandlung mit sulfonylharnstoffer. Schweiz Med Wochenschr 1971;71: 1013–22
Fuccella LM, Tamassia V, Valzelli G. Metabolism and kinetics of the hypo-glycaemic agent glipizide in man: comparison with glibenclamide. J Clin Pharmacol New Drugs 1973; 13: 68–75
Schmidt HA, Schoog M, Schweer KH, et al. Pharmacokinetics and pharmacodynamics as well as metabolism following orally and intravenously administered C14-glipizide, a new antidiabetic. Diabetologia 1973; 9: 320–30
Balant L, Zahnd G, Gorgia A, et al. Pharmacokinetics of glipizide in man: influence of renal insufficiency. Diabetologia 1973; 9: 331–8
Campbell DB, Adrianssens P, Hopkins YW, et al. Pharmacokinetics and metabolism of gliclazide: a review. In Keen H, Gordon B, Williams JRB, editors. Gliclazide and the treatment of diabetes. Royal Society of Medicine Congress Series 20. London: Royal Society of Medicine, 1980: 71–82
Oida T, Yoshida K, Kagemoto, et al. The metabolism of gliclazide in man. Xenobiotica 1985; 15: 87–96
Campbell DB, Gordon BH, Ings RMJ, et al. The effect of renal disease on the pharmacokinetics of gliclazide in diabetic patients. Br J Pharmacol 1986; 21: 572–3
Koss FW, Kopitar Z, Hammer R. The pharmacokinetic profile of glurenorm. Diabetes Croat 1976; 5: 355–71
Mincu J. Results of a controlled trial of glurenorm compared with a standard substance in patients with renal insufficiency. Proceedings of the International Conference on Glurenorm: 1975 Mar 13–14; Cavtat, Yugoslavia: 48–54
Kopitar Z, Koss FW. Pharmacokinetic behaviour of ARDF 26, a new sulphonylurea. Proceedings of the International Conference on Glurenorm: 1975 Mar 13–14; Cavtat, Yugoslavia: 20–9
Uglesic A, Ljahnicky N. New findings during the clinical investigation of glurenorm in diabetics with and without renal insufficiency. Diabetologica Croat 1976; 5: 539–48
Buchele W, Kuhlmann H. Gliquidon in der antidiabetischan therapie nieren und leberinsuffizienten patienten. Med Welt 1978; 29: 897–900
Bianchetti G, Graziani G, Brancaccio D, et al. Pharmacokinetics and effects of propranolol in terminal uraemic patients undergoing regular dialysis treatment. Clin Pharmacokinet 1976; 1: 373–84
Sirtori CR, Franceschini G, Galli-Kienle M, et al. Disposition of metformin (N,N-dimethylbiguanide) in man. Clin Pharmacol Ther 1978; 24: 683–93
Pentikainen PJ, Neuivonen PJ, Penttila A. Pharmacokinetics of metformin after intravenous and oral administration to man. Eur J Clin Pharmacol 1979; 16: 195–202
Tucker GT, Casey C, Phillips PJ, et al. Metformin kinetics in healthy subjects and in patients with diabetes mellitus. Br J Clin Pharmacol 1981; 12: 235–46
Assan R, Heuclin Ch, Ganeval D, et al. Metformin-induced lactic acidosis in the presence of acute renal failure. Diabetologia 1977; 13: 211–7
Bailey CJ, Nattrass M. Treatment: metformin. Clin Endocrinol Metab 1988; 2: 455–76
Campbell IW. Sulphonylureas and metformin: efficacy and inadequacy. In: Bailey CJ, Flatt PR, editors. New antidiabetic drugs. London: Smith-Gordon, 1990: 33–51
Keen H. Glucomodulation: a new therapeutic approach. Pract Diabetes 1993 Nov/Dec; Suppl. 10: 55–9
Spengler M, Cagatay M. Assessment of efficacy and tolerability of acarbose (Glucobay®) by clinical data pool. In: Lefebvre PJ, Standl E, editors. New aspects in diabetes. Berlin: Walter de Grutjer, 1992:285-8
Chiasson J-L, Josse RG, Hunt JA, et al. The efficacy of acarbose in the treatment of patients with non-insulin-dependent diabetes mellitus. Ann Intern Med 1994; 121: 928–35
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Harrower, A.D.B. Pharmacokinetics of Oral Antihyperglycaemic Agents in Patients with Renal Insufficiency. Clin-Pharmacokinet 31, 111–119 (1996). https://doi.org/10.2165/00003088-199631020-00003
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-199631020-00003