Molecular action of methotrexate in inflammatory diseases

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Arthritis Research & Therapy

Edwin SL Chan and Bruce N Cronstein

Division of Clinical Pharmacology, NYU School of Medicine, New York, NY,

USA

Arthritis Res 2002, 4:266-273

" Molecular action of methotrexate in inflammatory diseases " :

Proposed mechanisms of action of methotrexate

... Low-dose methotrexate was introduced for the treatment of RA

because of its presumed antiproliferative properties, although it was

unclear how inhibiting proliferation of the lymphocytes thought to be

responsible for synovial inflammation in RA for one day a week might

lead to effective suppression of disease activity. However, it soon

became clear that inhibition of folic acid metabolism could not be

completely responsible for the anti-inflammatory effect of methotrexate.

During the past 15 years, it has become clear that administration of

folic acid in doses of 1-5 mg per day helps to prevent much of the

toxicity of methotrexate without interfering with the anti-inflammatory

efficacy of the drug, whereas very high doses of folinic acid also

prevent methotrexate toxicity but may interfere with its efficacy

[7-20]. There are two potential explanations for the capacity of high

doses of folinic acid to reverse the therapeutic effects: first, folinic

acid may bypass the effects of methotrexate on reduction of folic acid

and thereby bypass the therapeutic effects of the drug; alternatively,

folinic acid but not folic acid may compete with methotrexate for a

single transport site into the cell (Fig. 1) and may thus interfere with

cellular uptake of methotrexate [21]. Moreover, the expected inhibition

of cellular proliferation is manifested as bone marrow suppression, and

oral and gastrointestinal ulcers, and may require lowering the dose of

the drug and, usually, the efficacy of the therapy, suggesting that

inhibition of cellular proliferation alone is not responsible for the

anti-inflammatory effects of methotrexate. Thus, folate antagonism

appears to play, at most, a minimal role in the anti-inflammatory

mechanism of methotrexate....

http://arthritis-research.com/content/4/4/266

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Mayo Clinic in Rochester

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