Methotrexate is a folate antimetabolite that inhibits di-hydrofolate reductase and other folate-dependent enzymes in cells. The absorption, metabolism, and excretion of methotrexate are fully described in Chapter 56. When given in high doses, methotrexate exerts potent suppressing action on cellular and humoral immunity (see Chapter 57). At the low doses used in the therapy of rheumatoid arthritis, methotrexate appears to be acting more as an antiinflammatory agent than as an im-munosuppressant. Methotrexate inhibits folate-depend-ent enzymes involved in adenosine degradation, increasing concentrations of extracellular adenosine. Adenosine acts via cell surface receptors to inhibit the production of inflammatory cytokines such as TNF-a and IFN-7. Methotrexate also decreases the production of inflammatory prostaglandins and proteases, though a direct action on the COX enzymes has not been noted.
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