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In vivo decline of methotrexate and methotrexate polyglutamates in age-fractionated erythrocytes

  • Original Articles
  • Methotrexate, Erythrocyte, Lymphoblastic Leukemia
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Summary

Methotrexate (MTX) accumulates in erythrocytes (ery) during weekly MTX administration, and the ery-MTX concentration reaches a steady state after 4–6 weeks. In order to study MTX accumulation and metabolism to polyglutamate derivatives in different age populations of red blood cells, we took erythrocytes from 12 children with ALL who were receiving maintenance treatment with MTX and 6-MP and separated them according to age on a discontinuous Percoll gradient. When the erythrocytes of these children were separated according to specific gravity a normal distribution was obtained. Age fractionation was confirmed by the exponential decline of the erythrocyte aspartate aminotransferase (ery-ASAT) and by the reticulocyte counts. The ery-MTX declined with increasing red blood cell age in an exponential manner no different from the decline of the ery-ASAT. The youngest population of red blood cells contained 2.3–5.9 (mean 3.8) times more MTX than the oldest population. By linear regression analysis the t1/2 of the ery-MTX was 19–79 days (mean 37 days). The ery-MTX t1/2 seemed to be directly related to the amount of MTX which had been metabolized to MTX-glu3-5. The decline of the ery-MTX was predominantly due to selective disappearance of MTX-glu1+2, whereas MTX-glu3-5 changed to a much lesser extent with advancing red blood cell age. The present investigation showed that steady-state ery-MTX concentration was determined by (1) the amount of MTX added to the circulation by the reticulocytes, (2) the in vivo loss predominantly of MTX with low numbers of glutamyl derivatives from erythrocytes, and (3) the loss of MTX from destroyed red blood cells. The observed in vivo disappearance of MTX from erythrocytes offers a possible explanation of the observation that the ery-MTX steady state was reached after 4–6 weeks of unaltered weekly MTX treatment.

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Authors and Affiliations

  1. Department of Pediatrics, Aarhus Kommunehospital, DK 8000, Aarhus, C, Denmark

    Henrik Schrøder & Troels Herlin

  2. Department of Clinical Chemistry, Aarhus Kommunehospital, Denmark

    Henrik Schrøder

  3. Department of Dermatovenereology, Marselisborg Hospital, Denmark

    Karsten Fogh & Troels Herlin

Authors
  1. Henrik Schrøder
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  2. Karsten Fogh
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  3. Troels Herlin
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The present work was supported by grant no. 12-6387 from the Danish Medical Research Council and by grants from the Institute of Experimental and Clinical Research, Universty of Aarhus Denmark

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Schrøder, H., Fogh, K. & Herlin, T. In vivo decline of methotrexate and methotrexate polyglutamates in age-fractionated erythrocytes. Cancer Chemother. Pharmacol. 21, 150–155 (1988). https://doi.org/10.1007/BF00257363

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  • DOI: https://doi.org/10.1007/BF00257363

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