When cellular proliferation in malignant tissue is greater than in most normal tissues, methotrexate may impair malignant growth without irreversible damage to normal tissues. In adults, oral absorption appears to be dose dependent. After absorption, methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidine synthetase. Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration.
Renal excretion occurs by glomerular filtration and active tubular secretion.
Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally or parenterally. The most common adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other adverse reactions include anaphylaxis, malaise, undue fatigue, chills and fever, dizziness, decreased resistance to infection. Use with extreme caution in the presence of infection, peptic ulcer, ulcerative colitis, debility, and in extreme youth and old age. The high potential toxicity of this drug is usually dose-related.