methotrexate

Modality

small molecule

Mechanism

12.1 Mechanism of Action Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate. The mechanism of action in rheumatoid arthritis and in psoriasis is unknown.

Targets

Dihydrofolate reductase, Thymidylate synthase

Storage

—

Approved

psoriasis — FDA

In trial

atopic dermatitis, psoriasis, alopecia areata, vitiligo, chronic urticaria

Sources

DailyMed (FDA label)DrugBank ClinicalTrials.gov

Last verified

2026-06-14

Mechanism of action

Methotrexate label (FDA, 2024)

drugtargetsignalingeffectorcellularphenotype⊣ red bar = blocked/reduced by drug

Monitoring & workup

Baseline workup

•CBC with differential
•CMP (LFTs, Cr)
•HBV sAg + core Ab; HCV Ab
•HCG if female of childbearing potential
•For azathioprine: TPMT/NUDT15 genotype or activity

Ongoing monitoring

•CBC + LFT + Cr every 2–4 weeks x initial, then every 8–12 weeks
•Consider FibroScan / Pro-C3 with cumulative dose (MTX)
•Avoid live vaccines; counsel on alcohol/teratogenicity