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Comprehensive Evaluation of the Effectiveness and Safety of Placenta-Targeted Drug Delivery Using Three Complementary Methods
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Folate and methotrexate polyglutamate tissue levels in rhesus monkeys following chronic low-dose methotrexate

N J Winick, B A Kamen, F M Balis

    Cancer Drug Delivery
    |January 1, 1987
    PubMed

    Insights

    Chronic methotrexate (MTX) treatment in monkeys led to significant accumulation of MTX polyglutamates and a 90% loss of brain folate. These findings suggest a link between folate depletion and MTX neurotoxicity.

    Area of Science:

    • Pharmacology
    • Toxicology
    • Neuroscience

    Background:

    • Methotrexate (MTX) is crucial for acute lymphoblastic leukemia treatment but causes hepatic and neurologic toxicity.
    • MTX is metabolized into polyglutamated derivatives (MTXGlun) with extended intracellular persistence.
    • MTXGlun may drive toxicity via cellular metabolism disruption or folate homeostasis imbalance.

    Purpose of the Study:

    • To investigate the long-term effects of chronic MTX administration on tissue MTX, MTXGlun, and folate levels.
    • To explore the relationship between MTX metabolite accumulation and folate depletion in various tissues.

    Main Methods:

    • Three monkeys received weekly intramuscular MTX for one year.
    • Tissue samples from liver, kidney, brain, and testis were analyzed for MTX, MTXGlun, and total folate concentrations.

    Main Results:

    • Over 80% of accumulated MTX in tissues existed as polyglutamated forms (MTXGlun), primarily MTXGlu3-5, with detectable MTXGlu6-7.
    • MTX-treated animals exhibited a 90% reduction in total folate levels within brain tissue.
    • Significant levels of MTX and MTXGlun were found across all measured tissues.

    Conclusions:

    • Chronic MTX treatment results in substantial accumulation of its polyglutamated metabolites.
    • Severe depletion of brain folate occurs following long-term MTX exposure.
    • The observed folate loss in brain tissue warrants further investigation regarding its contribution to MTX-induced neurotoxicity.

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