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High-dose 7-hydroxymethotrexate: Acute toxicity and lethality in a rat model

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Abstract

To elucidate mechanisms for methotrexate (MTX)-induced renal and hepatic toxicity, we investigated the acute effects of bolus plus continuous infusion of up to 0.4 g/kg 7-hydroxymethotrexate (7-OH-MTX) in the rat. We demonstrate for the first time in any species the occurrence of acute lethal toxicity within a few hours after 7-OH-MTX administration. Serum concentrations of 7-OH-MTX measured at the time of death were 1.4 mM (mean), about one-half of those achieved in some patients after infusion of high-dose MTX (HD-MTX) in the clinic. The data suggest an approximate LD50 (the dose lethal to 50% of the study population) of 0.3 g/kg and a steep dose/ lethality curve for 7-OH-MTX. Moreover, acute renal and hepatic toxicity occurred as evidenced by severe morphological findings and increased serum levels of creatinine and liver transaminases. In all rats subjected to continuous infusion of 7-OH-MTX, yellow microscopic precipitations were apparent in the kidney tubules. Crystallization was also seen in bile ducts of the liver in some of the rats. These results further support that the formation of 7-OH-MTX is disadvantageous and that reported attempts to prevent its formation during MTX treatment are warranted.

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Author notes

  1. Jarle Aarbakke

    Present address: Department of Pharmacology, Institute of Medical Biology, University of Tromsø, N-9037, Tromsø, Norway

Authors and Affiliations

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

    Eivind Smeland & Ole Martin Fuskevåg

  2. Department of Chemistry, Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway

    Kirsten Nymann & John Sigurd Svendsen

  3. Department of Morphology, Institute of Medical Biology, University of Tromsø, Tromsø, Norway

    Randi Olsen & Sigurd Lindal

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

    Roy M. Bremnes

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  1. Eivind Smeland
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  2. Ole Martin Fuskevåg
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  3. Kirsten Nymann
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  5. Randi Olsen
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  6. Sigurd Lindal
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This study was financially supported by the Norwegian Cancer Society, the Erna and Olav Aakre Foundation for Cancer Research, and the Norwegian Research Council

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Smeland, E., Fuskevåg, O.M., Nymann, K. et al. High-dose 7-hydroxymethotrexate: Acute toxicity and lethality in a rat model. Cancer Chemother Pharmacol 37, 415–422 (1996). https://doi.org/10.1007/s002800050406

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  • DOI: https://doi.org/10.1007/s002800050406

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