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Inhibition of 7-hydroxymethotrexate formation by amsacrine

  • Original Articles
  • Methotrexate, 7-Hydroxymethotrexate, Amsacrine
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Summary

The inhibition of methotrexate (MTX) biotransformation to 7-hydroxymethotrexate (7-OH-MTX) by 4′-(9-acridinylamino)-methanesulfon-m-anisidide (mAMSA) was studied in bile-drained rats in vivo and in incubates of isolated rat hepatocytes and rat-liver homogenate in vitro. In vivo, i.v. administration of 10 mg/kg mAMSA prior to [3H]-MTX infusion (50 mg/kg) led to a significant alteration in 7-OH-MTX kinetics. 7-OH-MTX peak concentrations and AUC in bile and serum were reduced by 75% and the recovery of MTX as 7-OH-MTX in bile and urine decreased by 70%, whereas MTX pharmacokinetics remained unaltered. In suspensions of isolated hepatocytes. 10 μm mAMSA led to a 54% decrease in 7-OH-MTX formation. However, the hepatocellular influx and efflux of MTX was not perturbed by mAMSA. Preincubation of rat-liver homogenates with 1.25–10 μm mAMSA reduced the formation of 7-OH-MTX by up to 73%. mAMSA appeared to inhibit MTX hydroxylation competitively, exhibiting aK iof 3 μm. Due to its inhibition of the MTX-oxidizing system, mAMSA may be beneficial in combination chemotherapy with MTX by reducing 7-OH-MTX-associated toxicity and, possibly, enhancing the cytotoxic effects of MTX.

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Authors and Affiliations

  1. Department of Biochemistry, Institute of Medical Biology, University of Tromsø, N-9001, Tromsø, Norway

    Nils P. Willassen

  2. Department of Oncology, Institute of Clinical Medicine, University of Tromsø, N-9001, Tromsø, Norway

    Erik Wist

  3. Department of Pharmacology, Institute of Medical Biology, University of Tromsø, P. O. Box 977, N-9001, Tromsø, Norway

    Roy M. Bremnes, Eivind Smeland & Jarle Aarbakke

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  1. Roy M. Bremnes
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  2. Eivind Smeland
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  3. Nils P. Willassen
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  4. Erik Wist
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  5. Jarle Aarbakke
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This study was financially supported by the Norwegian Cancer Society and the Erna and Olav Aakre Foundation for Cancer Research

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Bremnes, R.M., Smeland, E., Willassen, N.P. et al. Inhibition of 7-hydroxymethotrexate formation by amsacrine. Cancer Chemother. Pharmacol. 28, 377–383 (1991). https://doi.org/10.1007/BF00685693

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  • DOI: https://doi.org/10.1007/BF00685693

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