Toxicology of Sulfonylureas

  • F. Hartig
  • K. H. Langer
  • W. Rebel
  • F. H. Schmidt
  • E. Schütz
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 119)


Since 1958, Hoechst AG, Frankfurt, and Boehringer Mannheim GmbH have synthesized and pharmacologically tested a large number of sulfonylurea analogues which elicit hypoglycemic activity in the milligram range and in some cases at less than 0.1mg/kg body weight. Glibenclamide (HB419) was chosen from a group of the most potent compounds for joint research in 1964 and introduced onto the market as Daonil by Hoechst and as Euglucon by Boehringer (Hebold et al. 1969a, b; Mitsukami et al. 1969).


Positive Inotropic Effect Canine Femoral Artery TPase Activity Isolate Tissue Preparation Sister Chromatid Exchange Test 
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  1. Achelis JD, Hardebeck K (1955) Über eine neue blutzuckersenkende Substanz. Dtsch Med Wochenschr 80:1452–1455PubMedCrossRefGoogle Scholar
  2. Ambrogi V, Bloch K, Daturi S, Griggi P, Logemann W, Mandelli V, Parenti MA, Rabini T, Usardi MM, Tommasini R (1971) Pharmacological study on a new oral antidiabetic: N-4-beta-(5-methylpryrazine-2-carboxamido)ethylebenzenesul-fonyl-n’-cyclohexylurea or K4024. Arzneimittelforschung 21(2):208–215.Google Scholar
  3. Baeder C, Sakaguchi T (1969) Teratologische Untersuchungen mit HB 419, Arzneimittel Forsch 1419–1420Google Scholar
  4. Bänder A (1971) Zur Pharmakologie und Toxikologie der blutzuckersenkenden Sulfonamide. Handbuch der experimentellen Pharmakologie. Springer, Berlin Heidelberg New York, pp 318–401Google Scholar
  5. Ballagi-Pordány G, Koltai M-Z, Aranyi Z, Pogátsa G (1990) Direct cardiovascular effect of hypoglycemic sulphonylurea compounds. Diabetologia 33 [Suppl]:A53Google Scholar
  6. Brown JD, Brown ME (1977) The effect of tolbutamide on contractility and cyclic adenosine 3’:5’-monophosphate concentration in the intact beating rat heart. J Pharmacol Exp Ther 200:166–173PubMedGoogle Scholar
  7. Curtis GP, Setchfield J, Lucchesi BR (1975) The cardiac pharmacology of tolbutamide. J Pharmacol Exp Ther 194:264–273PubMedGoogle Scholar
  8. Duhault J, Boulanger M, Tisserand F, Beregi L (1972) The pharmacology of S 1072, a new highly effective oral antidiabetic drug with unusual properties. Arzneimittelforschung (Drug Res) 22:1682–1685Google Scholar
  9. Dulin WE, Oster HL, McMahon FG (1961) A new high potency antidiabetic sulfonylurea [n-(l-hexahydro-l-azepinyl)-N’-p-tolylsulfonylurea]. Proc Soc Exp Biol 107:245–248PubMedCrossRefGoogle Scholar
  10. Findlay I (1992) Effects of pH upon the inhibition by suphonylurea drugs of ATP-sensitive K+ channels in cardiac muscle. J Pharmacol Exp Ther 262:71–79PubMedGoogle Scholar
  11. Heboid G (1971) Experimentelle, geschlechtsdifferente Beeinflussung der Langer-hans’schen Inseln des Pankreas. Habilitationsschrift, University of HeidelbergGoogle Scholar
  12. Heboid G, Scholz J, Schütz E, Czerwek H, Sagagushi T, Brunk R, Notdurft H, Kief H, Bäder C, Hartig F (1969a) Experimental investigations of the new sulfonylurea-derivate glibenclamide Hb 419. Horm Metab Res 1:4–10Google Scholar
  13. Heboid G, Scholz J, Schütz E, Czerwek H, Brunk R (1969b) Verträglichkeitsprüfungen von Hb 419 im Tierversuch. Arzneimittelforschung 19:1404–1413Google Scholar
  14. Herman EH, Krop S, Jordan W (1982) Tolbutamide enhancement of ouabain cardiotoxicity in rabbits. Pharmacology 24:111–117PubMedCrossRefGoogle Scholar
  15. Hoffmann-La Roche (1985) Basic documentation on Glutril. Hoffmann-La Roche, Basel, pp 1–15Google Scholar
  16. Iida H, Kast A, Tsunenari Y (1976) Studies on the teratogenicity of a new sulfonylurea derivative (ARDF 26 SE) in rats and rabbits. Pharmocometrics 11:119–131Google Scholar
  17. Kast A, Tsunenari Y, Honma M, Nishikawa J, Shibata T, Torii M (1975) Toxico-logical tests of a new sulfonylurea derivate (ARDF 26 SE) in rats, mice and rabbits. Pharmacometrics 10:383–394Google Scholar
  18. Kiso To Rinsho (1972) Clinical report (Yubunsh Co). 6:1925Google Scholar
  19. Kleiss D, Rech M (1977) Langzeituntersuchungen an alloxandiabetischen Kaninchen — Stoff-wechselverhalten, Allgemeinbefinden, Kreislaufuntersuchungen und Organbefunde — unter chronischer Gabe von Tolbutamid und Methoxy-Methyl-Indolcarbonsäure. Dissertation, University of HeidelbergGoogle Scholar
  20. Krall LP (1984) Glyburide (DiaBeta®): a new second generation hypoglycemic agent. Clin Ther 6(6):746–762PubMedGoogle Scholar
  21. Kramer JH, Lampson WG, Schaffer SW (1983) Effect of tolbutamide on myocadial anergy metabolism. Ann J Physiol 245:H313–H319Google Scholar
  22. Kramer M, Hecht G, Lanecker H, Harwart A, Richter KD, Gloxhuber C (1964) Pharmako-logie des 2-Benzolsulfonamido-5(β- methoxy-äthoxy)-pyrimidins (Glycodiazin), einer neuen blutzuckersenkenden Verbindung. Arzneimittelforschung 14:377–385PubMedGoogle Scholar
  23. Lampson WG, Kramer JH, Schaffer SW (1985) Effect of tolbutamide on myocardial energy metabolism of the ischemic heart. Biochem Pharmacol 34:803–809PubMedCrossRefGoogle Scholar
  24. Lebovitz HE, Melander A (1992) Sulfonylureas: basic aspects and clinical uses. In: Alberti KGMM, DeFronzo RA, Keen H, Zimmet P (eds) International textbook of diabetes mellitus. Wiley, New YorkGoogle Scholar
  25. Lee KC, Wilson RA, Randall DC, Altiere RJ, Kiritsy-Ray JA (1988) An analysis of the haemodynamic effects of tolbutamide in conscious dogs. Clin Exp Pharmacol Physiol 15:379–390PubMedCrossRefGoogle Scholar
  26. Lorch E, Gey KF, Sommer P (1972) Glibornurid, ein neues hochwirksames Antidiabetikum Pharmakologische und biochemische Vergleichsuntersuchungen an verschiedenen Tierspezies und an tierexperimentellen Modellen. Arzneimittelforschung (Drug Res) 22(12a):2154–2163Google Scholar
  27. Maha GE, Kirtley WR, Root MA, Anderson RC (1962) Acetohexamide, preliminary report on a new oral hypoglycemic agent. Diabetes 11:83–90PubMedGoogle Scholar
  28. McKean, Branz AJ (1992) Influence of ATP-sensitive potassium channel blocker on hypoxia-induced damage of isolated guinea pig heart. Gen Pharmacol 23: 921–923PubMedCrossRefGoogle Scholar
  29. Mitsukami K, Myamoto M, Hayashi S, Kobayashi T, Sukurai M, Sakagushi T (1969) Toxikologische Untersuchungen von N-4-[2-(5-cholor-2-methoxy-benzamido)-acetyl]phenylsulfonyl-N-cyclohexylharnstoff (Hb 419). Arzneimittelforschung 19:1413–1419Google Scholar
  30. NCI report (1977a) Bioassay of acetohexamide for possible carcinogenicity (CAS no 968 81–0)Google Scholar
  31. NCI report (1977b) Bioassay of tolazamide for possible carcinogenicity (CAS no 1156–19-0)Google Scholar
  32. NCI Carcinogenesis Bioassay (1978) Chlorpropamide (NCITR* NCI-CG-TR-45,78); tolbutamide (NCITR* NCI-CG-TR-31,77)Google Scholar
  33. Pfeiffer EF (1984) Are the “second generation” oral hypoglycemic agents really different. Acta Diabetol Lat 21(l):l-32Google Scholar
  34. Renner HW, Münzinger R (1980) Mutagenicity of sulphonylureas. Mutat Res 77: 349–355PubMedCrossRefGoogle Scholar
  35. Schad H, Heimisch W, Maier-Rudolph W, Mendier M (1993) Effect of glibenclamide on myocardial blood flow and function. Eur J Physiol 422 [Suppl 1]:R111Google Scholar
  36. Schaffer SW, Poole CG, Lampson WG, Kramer JH (1981) Effect of tolbutamide on the mechanical function of the isolated rat heart subjected to global ischemia. J Mol Cell Cardiol 13:341–345PubMedCrossRefGoogle Scholar
  37. Schärer K, Hummler H (1971) Toxicological experiments with drugs of the sulfonylurea type in animals. In: Dubach UC, Bückert A (eds) Recent hypoglycemic sulfonylureas, mechanisms of action and clinical indications. Huber, Bern, pp 163–170Google Scholar
  38. Schneider JA, Salgado ED, Jäger D, Delahunt C (1959) The pharmacology of chlorpropamide. Ann N Y Acad Sci 74:427–442PubMedCrossRefGoogle Scholar
  39. Scholz J, Bänder A (1956) Über die orale Behandlung des Diabetes mellitus mit N-[4-Methylbenzolsulfonyl]-N′-butylharnstoff (D860), Pharmakologie. Dtsch Med Wochenschr 81:825–826Google Scholar
  40. Tan BH, Wilson GL, Schaffer SW (1984) Effect of tolbutamide on myocardial metabolism and mechanical performance of the diabetic rat. Diabetes 33: 1138–1143PubMedCrossRefGoogle Scholar
  41. Tettenborn D (1974) Zur Toxikologie von Glisoxepid, einem neuen oralen Antidiabetikum. Ergebnisse der Tieversuche. Arzneimittelforschung (Drug Res) 24:409–418Google Scholar
  42. University Group Diabetes Program (1970) A study of the effects of hypoglycemic agents on vascular complications in patients with adult onset. Diabetes 19 [Suppl II]:789–830Google Scholar
  43. Wales JK, Grant AM, Wolff FW (1971) The effect of tolbutamide on blood pressure. J Pharmacol Exp Ther 178:130–140PubMedGoogle Scholar
  44. Warnik PR, Davis FB, Davis PJ, Mylotte KM, Blas SD (1986) Differential activities of tolbutamide, tolazamide, and glyburide in vitro on rabbit myocardial membrane Ca2+-transporting ATPase activity. Diabetes 35:1044–1048CrossRefGoogle Scholar
  45. Watson WAF, Petrie JC, Galloway DB, Bullock I, Gilbert JC (1976) In vivo cytogenetic activity of sulphonylurea drugs in man. Mutat Res 38:71–80PubMedCrossRefGoogle Scholar
  46. Wu CF, Haider B, Ahmed SS, Oldewurtel HA, Lyons MM, Regan TJ (1977) The effects of tolbutamide on the myocardium in experimental diabetes. Circulation 55:200–205PubMedCrossRefGoogle Scholar
  47. Yasuba M, Matsuoka N, Iida M, Maeda K, Nishiwaki T, Ueda N, Ohnishi K, Tatsumi H, Hashimoto M (1981). Acute, subacute, and long-term toxicity studies of gliclazide in diabetic animals. Yakuri To Chiryo 9(ll):4497–4520Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1996

Authors and Affiliations

  • F. Hartig
  • K. H. Langer
  • W. Rebel
  • F. H. Schmidt
  • E. Schütz

There are no affiliations available

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