Skip to main content
SpringerLink
Log in

Methimazole as a protectant against cisplatin-induced nephrotoxicity using the dog as a model

  • Original Articles
  • Methimazole, Cisplatin, Nephrotoxicity
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

The protective effect of methimazole, a commonly used antithyroid drug, on cisplatin-induced nephrotoxicity was studied. Eight dogs received 80 mg/m2 cisplatin i.v. without saline prehydration. Dogs were randomized into two groups of four dogs each: one group received 40 mg/kg methimazole i.p. at 30 min prior to and 4 h after cisplatin delivery, and the other group received saline placebo i.p. Methimazole protected dogs against the in vivo nephrotoxicity elicited by cisplatin as evidenced by clinicopathologic and histopathologic indices. Protection was not complete, as methimazole-treated animals developed mild histopathologic renal changes. Measures of renal oxidative stress did not differ between the two groups at day 5 following cisplating treatment. No difference was noted for serum thyroxine concentrations before or after therapy in either group; however, serum levels of 3,5,3′-triiodothyronine were significantly higher on day 5 in both groups of dogs receiving cisplatin, regardless of whether they received methimazole or not. Methimazole as used in this study was found to be well tolerated in dogs over the short term, with no significant clinical or clinicopathologic toxicity being observed. The results of this study support the additional evaluation of methimazole as a protectant against cisplatin-induced nephrotoxicity using the dog as a model.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Alexander WD, Evans V, Macaulay A, Gallagher TF, Londono J (1969) Metabolism of35S-labelled antithyroid drugs in man. BMJ 2: 290

    Google Scholar 

  2. Anderson ME, Naganuma A, Meister A (1990) Protection against cisplatin toxicity by administration of glutothione ester. FASEB J 4: 3251

    Google Scholar 

  3. Borch RF, Markman M (1989) Biochemical modulation of cisplatin toxicity. Pharmacol Ther 41: 371

    Google Scholar 

  4. Brodey RS (1979) The use of naturally occurring cancer in domestic animals for research into human cancer: general considerations and a review of canine skeletal osteosarcoma. Yale J Biol Med 52: 345

    Google Scholar 

  5. Brown WD (1960) Reduction of protein disulfide bonds by sodium borohydride. Biochim Biophys Acta 44: 365

    Google Scholar 

  6. Cavalieri RR, Pitt-Rivers R (1981) The effects of drugs on the distribution and metabolism of thyroid hormones. Pharmacol Rev 33: 55

    Google Scholar 

  7. Cvitkovic E, Spualding J, Bethune V, Martin J, Whitmore WF (1977) Improvement ofcis-dichlorodiammineplatinum (NSC 119875): therapeutic index in an animal model. Cancer 39: 1357

    Google Scholar 

  8. DiMonte D, Ross D, Bellomo G, Eklow L, Orrenius S (1984) Alerations in intracellular thiol homeostasis during the metabolism of menadione by isolated rat hepatocytes. Arch Biochem Biophys 235: 334

    Google Scholar 

  9. Dobyan DC, Levi J, Jacobs J, Kosek J, Wiener MW (1980) Mechanisms ofcis-platinum nephrotoxicity. II. Morphological observations. J Pharmacol Exp Ther 213: 551

    Google Scholar 

  10. Elfarra AA (1993) Aliphatic halogenated hydrocarbons. In: Hook JB, Goldstein R (eds) Toxicology of the kidney. Raven, New York, pp 387–413

    Google Scholar 

  11. Fregly MJ (1961) Increased water exchange in rats treated with antithyroid drugs. J Pharmacol Exp Ther 134: 69

    Google Scholar 

  12. Hardie EM, Page RL, Williams PL, Fischer WD (1991) Effect of time of cisplatin administration on its toxicity and pharmacokinetics in dogs. Am J Vet Res 52: 1821

    Google Scholar 

  13. Hannemann J, Bauman K (1988) Cisplatin-induced lipid peroxidation and decreased gluconeogenesis in rat kidney cortex: different effects of antioxidants and radical scavengers. Toxicology 51: 119

    Google Scholar 

  14. Kraigel SA, Madewell BR, Simonson E, Gregory CR (1991) Osteogenic sarcoma and cisplatin chemotherapy in dogs: 16 cases (1986–1989). J Am Vet Med Assoc 199: 1057

    Google Scholar 

  15. Labato MA, Ross LA (1991) Plasma disappearance of creatinine as a renal function test in the dog. Res Vet Sci 50: 253

    Google Scholar 

  16. Larue SM, Withrow SJ, Powers BE, Wrigley RH, Gillette EL, Schwarz PD, Straw RC, Richter SL (1989) Limb-sparing treatment for osteosarcoma in dogs. J Am Vet Med Assoc 195: 1734

    Google Scholar 

  17. Litterst C, Torres IJ, Guarino AM (1977) Plasma levels and organ distribution of platinum in the rat, dog, and dogfish shark following single intravenous administration ofcis-dichlorodiammineplatinum(II). J Clin Hematol Oncol 7: 169

    Google Scholar 

  18. Maher JF (1976) Toxic nephropathy. In: Brenner BM, Rector FC (eds) The kidney, vol. 2. W. B. Saunders, Philadelphia, p 1355

    Google Scholar 

  19. Montine TJ, Borch RF (1990) Role of endogenous sulfur-containing nucleophiles in an in vitro model ofcis-diamminedichloroplatinum(II)-induced nephrotoxicity. Biochem Pharmacol 39: 1751

    Google Scholar 

  20. Ogilvie GK, Krawiec DR, Gelberg HB, Twardock AR, Reschke RW, Richardson BC (1988) Evaluation of a short-term saline diuresis protocol for the administration of cisplatin. Am J Vet Res 49: 1076

    Google Scholar 

  21. Ogilvie GK, Moore AS, Curtis CR (1989) Evaluation of cisplatin-induced emesis in dogs with malignant neoplasia: 115 cases (1984–1987). J Am Vet Med Assoc 195: 1399

    Google Scholar 

  22. Ogilvie GK, Straw RC, Powers BE, Cooper MF, Withrow SJ (1991) Prevalence of nephrotoxicity associated with a short-term saline solution diuresis protocol for the administration of cisplatin to dogs with malignant tumors: 61 cases (1987–1989). J Am Vet Med Assoc 199: 613

    Google Scholar 

  23. Panciera DL, Post K (1992) Effect of oral administration of sulfadiazine and trimethoprin in combination on thyroid function in dogs. Can J Vet Res 56: 349

    Google Scholar 

  24. Peterson ME, Kintzer PP, Hurvitz AI (1988) Methimazole treatment of 262 cats with hyperthyroidism. J Vet Intern Med 2: 150

    Google Scholar 

  25. Pittman JA, Beschi RJ, Smitherman TC (1971) Methimazole: its absorption and excretion in man and tissue distribution in rats. J Clin Endocrinol Metab 33: 182

    Google Scholar 

  26. Quazi R, Chang AYC, Borch RF, Montine T, Dedon P, Olughner J, Bennett JM (1988) Phase I clinical and pharmacokinetic study of diethyldithiocarbamate as a chemoprotector from toxic effects of cisplatin. J Natl Cancer Inst 80: 1486

    Google Scholar 

  27. Reed DJ (1990) Glutathione: toxicological implications. Annu Rev Pharmacol Toxicol 30: 603

    Google Scholar 

  28. Sausen PJ, Elfarra AA (1990) Cysteine conjugate S-oxidase: characterization of a novel enzymatic activity in rat hepatic and renal microsomes. J Biol Chem 265: 6139

    Google Scholar 

  29. Sausen PJ, Elfarra AA, Cooley AJ (1992) Methimazole protection of rats against chemically induced kidney damage in vivo. J Pharmacol Exp Ther 260: 393

    Google Scholar 

  30. Schaeppi U, Heyman IA, Fleischman RW, Rosenkrantz H, Ilievski V, Phelan R, Cooney DA, Davis RD (1973)cis-Dichlorodiammineplatinum(II) (NSC-119 875): preclinical toxicologic evaluation of intravenous injection in dogs, monkeys and mice. Toxicol Appl Pharmacol 25: 230

    Google Scholar 

  31. Shapiro W, Fossum TW, Kitchell BE, Couto CG, Theilen GH (1988) Use of cisplatin for treatment of appendicular osteosarcoma in dogs. J Am Vet Med Assoc 192: 507

    Google Scholar 

  32. Sitar DS, Thornhill DP (1973) Methimazole: absorption, metabolism, and excretion in the albino rat. J Pharmacol Exp Ther 184: 432

    Google Scholar 

  33. Skellern GG, Stenlake JB, Williams WD (1973) The absorption, distribution, excretion and metabolism of2–14C-methimazole in rat. Xenobiotica 3: 121

    Google Scholar 

  34. Trepanier LA, Peterson ME, Aucoin DP (1991) Pharmacokinetics of intravenous and oral methimazole following single and multiple dose administration in normal cats. J Vet Pharmacol Ther 14: 367

    Google Scholar 

  35. Tune BM, Fravert D, Hsu CY (1989) Oxidative and mitochondrial toxic effects of cephalosporin antibiotics in the kidney. Biochem Pharmacol 38: 795

    Google Scholar 

  36. Withrow SJ, Powers BE, Straw RC, Wilkins RM (1991) Comparative aspects of osteosarcoma: dog versus man. Clin Orthop 270: 159

    Google Scholar 

  37. Zunino F, Pratesi G, Micheloni A, Cavalletti E, Sala F, Tofanetti O (1989) Protective effect of reduced glutathione against cisplatin-induced renal and systemic toxicity and its influence on the therapeutic activity of the antitumor drug. Chem-Biol Interact 70: 89

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive West, 53706, Madison, WI, USA

    David M. Vail, David L. Panciera, E. Gregory MacEwen & Steve A. Soergel

  2. Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, 53706, Madison, WI, USA

    Adnan A. Elfarra

  3. Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 53706, Madison, WI, USA

    A. James Cooley

  4. The Comprehensive Cancer Center, Department of Human Oncology, School of Medicine, University of Wisconsin-Madison, 53706, Madison, WI, USA

    David M. Vail & E. Gregory MacEwen

Authors
  1. David M. Vail
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adnan A. Elfarra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. James Cooley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David L. Panciera
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E. Gregory MacEwen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Steve A. Soergel
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This work was supported in part by Bristol-Myers Squibb Co. (Evansville, Ind.)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vail, D.M., Elfarra, A.A., Cooley, A.J. et al. Methimazole as a protectant against cisplatin-induced nephrotoxicity using the dog as a model. Cancer Chemother. Pharmacol. 33, 25–30 (1993). https://doi.org/10.1007/BF00686018

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00686018

Keywords

Search

Navigation