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Renal and hepatic toxicity after high-dose 7-hydroxymethotrexate in the rat

  • Original Articles
  • 7-Hydroxymethotrexate, Hepatic Toxicity
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Abstract

To examine directly the hepatic and renal toxicity of 7-hydroxymethotrexate (7-OH-MTX) without interference of the parent compound methotrexate (MTX), we purified and gave 100 mg/kg 7-OH-MTX to rats, a dose resulting in serum levels of 7-OH-MTX comparable with those achieved in the clinic after the administration of high-dose MTX (HD-MTX). After only 5 h, the 7-OH-MTX-treated rats demonstrated 2.6-fold increases in serum creatinine values and 2-fold elevations in serum aspartate aminotransferase (ASAT) levels as compared with the controls. Morphologic evidence of toxicity, however, was apparent only in the kidneys. Intraluminal cellular debris containing membranous material and deteriorated organelles was seen, but no precipitate of the delivered drug. The peak serum concentration of 7-OH was up to 939 μM, and concentrations of 7-OH-MTX declined triphasically, showing at1/2α value of 2.45 min, at1/2β value of 30.5 min, and a terminal half-life (t1/2γ) of 240 min. The total clearance value was 14.5 ml min−1 kg, and the postdistributional volume of distribution (Vβ) was 5070 ml/kg. Our results may indicate a direct toxic effect of 7-OH-MTX on kidney and liver cells.

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References

  1. Abelson HT, Garnick MB (1982) Renal failure induced by cancer chemotherapy. In: Rieselbach RE, Garnick MB (eds) Cancer and the kidney. Lea & Febiger, Philadelphia, p 769

    Google Scholar 

  2. Ahmad S, Shen F, Bleyer WA (1978) Methotrexate-induced renal failure and ineffectiveness of peritoneal dialysis. Arch Intern Med 138:1146

    Google Scholar 

  3. Banerjee AK, Lakhani S, Vincent M, Selby P (1988) Dose-dependent acute hepatitis associated with administration of high dose methotrexate. Hum Toxicol 7:561

    Google Scholar 

  4. Bertino JR (1985) Clinical use of methotrexate — with emphasis on use of high doses. Cancer Treat Rep 65 [Suppl 1]:131

    Google Scholar 

  5. Borsi JD, Sagen E, Romslo I, Moe PJ (1990) Comparative study of the pharmacokinetics of 7-hydroxymethotrexate after administration of methotrexate in the dose range of 0.5 g to 33.5 g/m2 in children with acute lymphoblastic leukemia. Med Pediatr Oncol 18:217

    Google Scholar 

  6. Breithaupt H, Kuenzlen E (1982) Pharmacokinetics of methotrexate and 7-hydroxymethotrexate following infusions of high-dose methotrexate. Cancer Treat Rep 66:1733

    Google Scholar 

  7. Breithaupt H, Kuenzlen E (1983) High-dose methotrexate for osteosarcoma: toxicity and clinical results. Oncology 40:85

    Google Scholar 

  8. Bremnes RM, Slørdal L, Wist E, Aarbakke J (1989) Formation and elimination of 7-hydroxymethotrexate in the rat in vivo after methotrexate administration. Cancer Res 49:2460

    Google Scholar 

  9. Bremnes RM, Slørdal L, Wist E, Aarbakke J (1989) Dose-dependent pharmacokinetics of methotrexate and 7-hydroxymethotrexate in the rat in vivo. Cancer Res 49:6359

    Google Scholar 

  10. Bremnes RM, Smeland E, Huseby N-E, Eide TJ, Aarbakke J (1991) Acute hepatotoxicity after high-dose methotrexate administration in rats. Pharmacol Toxicol 69:132

    Google Scholar 

  11. Chen M-L, Chiou WL (1981) Sensitive and rapid high-performance liquid chromatographic method for the simultaneous determination of methotrexate and its metabolite in plasma, saliva and urine. J Chromatogr 226:125

    Google Scholar 

  12. Committee on Enzymes, Scandinavian Society for Clinical Chemistry and Clinical Physiology (1974) Recommended methods for the determination of four enzymes in blood. Scand J Clin Lab Invest 33:291

    Google Scholar 

  13. Deray G, Khayat D, Cacoub P, Bourbouze R, Musset L, Baumelou A, Jacquillat C, Jacobs C (1989) The effects of diltiazem on methotrexate-induced nephrotoxicity. Eur J Clin Pharmacol 37:337

    Google Scholar 

  14. Erttman R, Bielack S, Landbeck G (1985) Kinetics of 7-hydroxymethotrexate after high-dose methotrexate therapy. Cancer Chemother Pharmacol 15:101

    Google Scholar 

  15. Evans WE, Crom WR, Abromowitch M, Dodge T, Look T, Bowman WP, George SL, Pui C-H (1986) Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia. Identification of a relation between concentration and effect. N Engl J Med 314:471

    Google Scholar 

  16. Fahrig L, Brasch H, Iven H (1989) Pharmacokinetics of methotrexate (MTX) and 7-hydroxymethotrexate (7-OH-MTX) in rats and evidence for the metabolism of MTX to 7-OH-MTX. Cancer Chemother Pharmacol 23:156

    Google Scholar 

  17. Farquhar D, Loo TL (1972) Synthesis and biologic evaluation of 7-hydroxymethotrexate, 7-methylaminopterin, and 7-methylmethotrexate. J Med Chem 15:567

    Google Scholar 

  18. Freeman-Narrod M, Kim JS, Ohanissian H, Mills K, Smiley JW, Djerassi I (1982) The effect of high-dose methotrexate on renal tubules as indicated by urinary lysozyme concentration. Cancer 50:2775

    Google Scholar 

  19. Goh TS, Wong KY, Lampkin B, O'Leary J, Gnarra D (1979) Evaluation of 24-hour infusion of high-dose methotrexate pharmacokinetics and toxicity. Cancer Chemother Pharmacol 3:177

    Google Scholar 

  20. Goren MP, Wright RK, Horowitz ME, Meyer WH (1986) Enhancement of methotrexate nephrotoxicity after cisplatin therapy. Cancer 58:2617

    Google Scholar 

  21. Iven H, Brasch H, Engster J (1985) Pharmacokinetics of methotrexate and 7-hydroxymethotrexate in rabbits. Cancer Chemother Pharmacol 15:115

    Google Scholar 

  22. Jacobs SA, Stoller RG, Chabner BA, Johns DG (1976) 7-Hydroxymethotrexate as a urinary metabolite in human subjects and rhesus monkeys receiving high dose methotrexate. J Clin Invest 57:534

    Google Scholar 

  23. Jacobs SA, Stoller RG, Chabner BA, Johns DG (1977) Dose-dependent metabolism of methotrexate in man and rhesus monkeys. Cancer Treat Rep 61:651

    Google Scholar 

  24. Jaffe N, Traggis D (1975) Toxicity of high-dose methotrexate (NSC-740) and citrovorum factor (NSC-3590) in osteogenic sarcoma. Cancer Chemother Rep 6:31

    Google Scholar 

  25. Johns DG, Loo TL (1967) Metabolite of 4-amino-4-deoxy-N 10-methyl-pteroylglutamic acid (methotrexate). J Pharm Sci 56:356

    Google Scholar 

  26. Johns DG, Iannotti AT, Sartorelli AC, Bertino JR (1966) The relative toxicities of methotrexate and aminopterin. Biochem Pharmacol 15:555

    Google Scholar 

  27. Lankelman J, Van der Klein E, Ramaekers F (1980) The role of 7-hydroxymethotrexate during methotrexate anti-cancer therapy. Cancer Lett 9:133

    Google Scholar 

  28. Perez C, Sutow WW, Wang YM, Herson J (1979) Evaluation of overall toxicity of high-dosage methotrexate regimens. Med Pediatr Oncol 6:219

    Google Scholar 

  29. Pitman SW, Frei E III (1977) Weekly methotrexate-calcium leucovorin rescue: effect of alkalinization on nephrotoxicity: pharmacokinetics in the CNS; and use in CNS non-Hodgkin's lymphoma. Cancer Treat Rep 61:695

    Google Scholar 

  30. Pitman SW, Parker LM, Tattersall MHN, Jaffe N, Frei E III (1975) Clinical trial of high-dose, methotrexate (NSC-740) with citrovorum factor (NSC-3590) — toxicologic and therapeutic observations. Cancer Chemother Rep 6:43

    Google Scholar 

  31. Price P, Thompson H, Bessell EM, Bloom HJG (1988) Renal impairment following the combined use of high-dose methotrexate and procarbazine. Cancer Chemother Pharmacol 21:265

    Google Scholar 

  32. Redetzki HM, Redetzki JE, Elias AL (1966) Resistance of the rabbit to methotrexate: isolation of a drug metabolite with decreased cytotoxicity. Biochem Pharmacol 15:425

    Google Scholar 

  33. Reggev A, Djerassi I (1988) The safety of administration of massive doses of methotrexate (50 g) with equimolar citrovorum factor rescue in adult patients. Cancer 61:2423

    Google Scholar 

  34. Ries F, Klastersky J (1986) Nephrotoxicity induced by cancer chemotherapy with special emphasis on cisplatin toxicity. Am J Kidney Dis 8:368

    Google Scholar 

  35. Rieselbach RE, Garnick MB (1993) Renal diseases induced by antineoplastic agents. In: Schrier RW, Gottschalk CW (eds) Diseases of the kidney, 5th edn. Little & Brown, Boston, p 1165

    Google Scholar 

  36. Slørdal L, Kolmannskog S, Prytz PS, Moe PJ, Aarbakke J (1986) Pharmacokinetics of methotrexate and 7-hydroxymethotrexate after high-dose (33.6 g/m2) methotrexate therapy. Pediatr Hematol Oncol 3:127

    Google Scholar 

  37. Slørdal L, Jæger R, Kjæve J, Aarbakke J (1988) Pharmacokinetics of 7-hydroxymethotrexate in the rat. Pharmacol Toxicol 63: 81

    Google Scholar 

  38. Stephen P, Schilsky A, Schilsky RL (1987) High-dose methotrexate: a critical reappraisal. J Clin Oncol 5:2017

    Google Scholar 

  39. Stoller RG, Jacobs SA, Drake JC, Lutz RJ, Chabner BA (1975) Pharmacokinetics of high-dose methotrexate (NSC-740). Cancer Chemother Rep 6:19

    Google Scholar 

  40. Von Hoff DD, Penta JS, Helman LJ, Slavik M (1977) Incidence of drug-related deaths secondary to high-dose methotrexate and citrovorum factor administration. Cancer Treat Rep 61:745

    Google Scholar 

  41. Wang Y-M, Fujimoto T (1984) Clinical pharmacokinetics of methotrexate in children. Clin Pharmacokinet 9: 335

    Google Scholar 

  42. Warkentin P, Coccia P, Ramsay N, Nesbit M, Krivit W (1978) Acute hepatocellular injury after high dose methotrexate (MTX) infusions. Proc Am Soc Clin Oncol 19:337

    Google Scholar 

  43. Warkentin P, Haseqawa O, Nesbit M, Krivit W, Coccia P (1979) High dose methotrexate (MTX) hepatotoxicity: significance of frequency of administration. Proc Am Assoc Cancer Res 20:98

    Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology, Institute of Medical Biology, University of Tromsø, N-9037, Tromsø, Norway

    Eivind Smeland, Anders Andersen, Ragnhild Jæger & Jarle Aarbakke

  2. Department of Morphology, Institute of Medical Biology, University of Tromsø, N-9037, Tromsø, Norway

    Roy M. Bremnes

  3. Department of Clinical Chemistry, Institute of Medical Biology, University of Tromsø, N-9037, Tromsø, Norway

    Tor J. Eide

  4. Department of Oncology, Institute of Clinical Medicine, University of Tromsø, N-9037, Tromsø, Norway

    Nils-E Huseby

Authors
  1. Eivind Smeland
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  2. Roy M. Bremnes
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  3. Anders Andersen
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  4. Ragnhild Jæger
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  5. Tor J. Eide
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  6. Nils-E Huseby
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  7. Jarle Aarbakke
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This study was supported financially by the Norwegian Cancer Society

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Smeland, E., Bremnes, R.M., Andersen, A. et al. Renal and hepatic toxicity after high-dose 7-hydroxymethotrexate in the rat. Cancer Chemother. Pharmacol. 34, 119–124 (1994). https://doi.org/10.1007/BF00685928

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  • DOI: https://doi.org/10.1007/BF00685928

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