Methotrate

Methotrate - General Information

An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [PubChem]

Pharmacology of Methotrate

Methotrate is an antineoplastic anti-metabolite. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Methotrate inhibits folic acid reductase which is responsible for the conversion of folic acid to tetrahydrofolic acid. At two stages in the biosynthesis of purines and at one stage in the synthesis of pyrimidines, one-carbon transfer reactions occur which require specific coenzymes synthesized in the cell from tetrahydrofolic acid. Tetrahydrofolic acid itself is synthesized in the cell from folic acid with the help of an enzyme, folic acid reductase. Methotrate looks a lot like folic acid to the enzyme, so it binds to it quite strongly and inhibits the enzyme. Thus, DNA synthesis cannot proceed because the coenzymes needed for one-carbon transfer reactions are not produced from tetrahydrofolic acid because there is no tetrahydrofolic acid. Methotrate selectively affects the most rapidly dividing cells (neoplastic and psoriatic cells). Methotrate is also indicated in the management of severe, active, classical, or definite rheumatoid arthritis.

Methotrate for patients

Patients should be informed of the early signs and symptoms of toxicity, of the need to see their physician promptly if they occur, and the need for close follow-up, including periodic laboratory tests to monitor toxicity. 

Both the physician and pharmacist should emphasize to the patient that the recommended dose is taken weekly in rheumatoid arthritis and psoriasis, and that mistaken daily use of the recommended dose has led to fatal toxicity. Patients should be encouraged to read the Patient Instructions sheet within the Dose Pack. Prescriptions should not be written or refilled on a PRN basis. 

Patients should be informed of the potential benefit and risk in the use of methotrexate. The risk of effects on reproduction should be discussed with both male and female patients taking methotrexate. 

Methotrate Interactions

Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity.

Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. 

Despite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis have usually included concurrent use of constant dosage regimens of NSAIDs, without apparent problems. It should be appreciated, however, that the doses used in rheumatoid arthritis (7.5 to 15 mg/week) are somewhat lower than those used in psoriasis and that larger doses could lead to unexpected toxicity. 

Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides. Renal tubular transport is also diminished by probenecid; use of methotrexate with this drug should be carefully monitored. 

Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria. 

Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with high and low dose methotrexate. Use of methotrexate with penicillins should be carefully monitored. 

The potential for increased hepatotoxicity when methotrexate is administered with other
hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with methotrexate and other potential hepatotoxins (e.g., azathioprine, retinoids, sulfasalazine) should be closely monitored for possible increased risk of hepatotoxicity.
Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate. 

Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate. Preliminary animal and human studies have shown that small quantities of intravenously administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and in humans, remain 1 - 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate. 

Folate deficiency states may increase methotrexate toxicity. Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by an additive antifolate effect. 

Methotrate Contraindications

Methotrexate can cause fetal death or teratogenic effects when administered to a pregnant woman. Methotrexate is contraindicated in pregnant women with psoriasis or rheumatoid arthritis and should be used in the treatment of neoplastic diseases only when the potential benefit outweighs the risk to the fetus. Women of childbearing potential should not be started on methotrexate until pregnancy is excluded and should be fully counseled on the serious risk to the fetus should they become pregnant while undergoing treatment. Pregnancy should be avoided if either partner is receiving methotrexate; during and for a minimum of three months after therapy for male patients, and during and for at least one ovulatory cycle after therapy for female patients.  

Because of the potential for serious adverse reactions from methotrexate in breast fed infants, it is contraindicated in nursing mothers. 

Patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease or other chronic liver disease should not receive methotrexate. 

Patients with psoriasis or rheumatoid arthritis who have overt or laboratory evidence of immunodeficiency syndromes should not receive methotrexate. 

Patients with psoriasis or rheumatoid arthritis who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anemia, should not receive methotrexate. 

Patients with a known hypersensitivity to methotrexate should not receive the drug. 

Additional information about Methotrate

Methotrate Indication: For the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole. Also for the treatment of severe psoriasis and severe, active, classical or definite rheumatoid arthritis.
Mechanism Of Action: Methotrate anti-tumor activity is a result of the inhibition of folic acid reductase, leading to inhibition of DNA synthesis and inhibition of cellular replication. The mechanism involved in its activity against rheumatoid arthritis is not known.
Drug Interactions: Acitretin Acitretin/etretinate increases the effect and toxicity of methotrexate
Etretinate Acitretin/etretinate increases the effect and toxicity of methotrexate
Amoxicillin The penicillin increases the effect and toxicity of methotrexate
Ampicillin The penicillin increases the effect and toxicity of methotrexate
Bacampicillin The penicillin increases the effect and toxicity of methotrexate
Carbenicillin The penicillin increases the effect and toxicity of methotrexate
Ciprofloxacin Ciprofloxacin increases methotrexate toxicity
Cisplatin Cisplatin increases methotrexate toxicity
Cloxacillin The penicillin increases the effect and toxicity of methotrexate
Cyclosporine Cyclosporine increases the effect and toxicity of methotrexate
Dicloxacillin The penicillin increases the effect and toxicity of methotrexate
Flucloxacillin The penicillin increases the effect and toxicity of methotrexate
Methicillin Acyl-Serine The penicillin increases the effect and toxicity of methotrexate
Mezlocillin The penicillin increases the effect and toxicity of methotrexate
Nafcillin The penicillin increases the effect and toxicity of methotrexate
Penicillin G The penicillin increases the effect and toxicity of methotrexate
Penicillin V The penicillin increases the effect and toxicity of methotrexate
Piperacillin The penicillin increases the effect and toxicity of methotrexate
Pivampicillin The penicillin increases the effect and toxicity of methotrexate
Ticarcillin The penicillin increases the effect and toxicity of methotrexate
Trimethoprim Timethoprim increases methotrexate toxicity
Procarbazine Increased nephrotoxicity with this combination
Rofecoxib Rofecoxib increases the levels of methotrexate
Probenecid Probenecid increases the effect and toxicity of methotrexate
Omeprazole Omeprazole increases the levels of methotrexate
Hydroxychloroquine Hydroxychloroquine increases the effect and toxicity of methotrexate
Aspirin The salicylate increases the effect and toxicity of methotrexate
Bismuth Subsalicylate The salicylate increases the effect and toxicity of methotrexate
Salicylate-magnesium The salicylate increases the effect and toxicity of methotrexate
Salicylate-sodium The salicylate increases the effect and toxicity of methotrexate
Salsalate The salicylate increases the effect and toxicity of methotrexate
Trisalicylate-choline The salicylate increases the effect and toxicity of methotrexate
Cholestyramine Decreased levels of methotrexate
Diclofenac The NSAID increases the effect and toxicity of methotrexate
Etodolac The NSAID increases the effect and toxicity of methotrexate
Fenoprofen The NSAID increases the effect and toxicity of methotrexate
Flurbiprofen The NSAID increases the effect and toxicity of methotrexate
Ibuprofen The NSAID increases the effect and toxicity of methotrexate
Indomethacin The NSAID increases the effect and toxicity of methotrexate
Ketoprofen The NSAID increases the effect and toxicity of methotrexate
Ketorolac The NSAID increases the effect and toxicity of methotrexate
Meclofenamic acid The NSAID increases the effect and toxicity of methotrexate
Mefenamic acid The NSAID increases the effect and toxicity of methotrexate
Nabumetone The NSAID increases the effect and toxicity of methotrexate
Naproxen The NSAID increases the effect and toxicity of methotrexate
Oxaprozin The NSAID increases the effect and toxicity of methotrexate
Phenylbutazone The NSAID increases the effect and toxicity of methotrexate
Piroxicam The NSAID increases the effect and toxicity of methotrexate
Sulindac The NSAID increases the effect and toxicity of methotrexate
Tiaprofenic acid The NSAID increases the effect and toxicity of methotrexate
Tolmetin The NSAID increases the effect and toxicity of methotrexate
Digoxin The antineoplasic agent decreases the effect of digoxin
Ethotoin The antineoplasic agent decreases the effect of hydantoin
Fosphenytoin The antineoplasic agent decreases the effect of hydantoin
Mephenytoin The antineoplasic agent decreases the effect of hydantoin
Phenytoin The antineoplasic agent decreases the effect of hydantoin
Doxycycline The tetracycline increases methotrexate toxicity
Tetracycline The tetracycline increases methotrexate toxicity
Sulfacytine The sulfamide increases the toxicity of methotrexate
Sulfadiazine The sulfamide increases the toxicity of methotrexate
Sulfadoxine The sulfamide increases the toxicity of methotrexate
Sulfamerazine The sulfamide increases the toxicity of methotrexate
Sulfamethazine The sulfamide increases the toxicity of methotrexate
Sulfamethizole The sulfamide increases the toxicity of methotrexate
Sulfamethoxazole The sulfamide increases the toxicity of methotrexate
Sulfapyridine The sulfamide increases the toxicity of methotrexate
Sulfathiazole The sulfamide increases the toxicity of methotrexate
Sulfisoxazole The sulfamide increases the toxicity of methotrexate
Sulfadimethoxine The sulfamide increases the toxicity of methotrexate
Food Interactions: Not Available
Generic Name: Methotrexate
Synonyms: MTX; N-Bismethylpteroylglutamic Acid; Methylaminopterinum; Methylaminopterin; Methotrexate Sodium; Amethopterin; Amethopterine; HDMTX; L-Amethopterin; Methopterin; Methotextrate; Methotrexat
Drug Category: Antirheumatic Agents; Immunosuppressive Agents; Dermatologic Agents; Antimetabolites; Abortifacient Agents; Antineoplastic Agents
Drug Type: Small Molecule; Approved

Other Brand Names containing Methotrexate: Abitrexate; Antifolan; Arbitrexate; Emtexate; Folex; Ledertrexate; Metatrexan; Methotrate; Mexate; Rheumatrex; Trexall;
Absorption: Generally well absorbed with a mean bioavailability of about 60%.
Toxicity (Overdose): Symptoms of overdose include bone marrow suppression and gastrointestinal toxicity. LD₅₀=43mg/kg(orally in rat).
Protein Binding: 50%, primarily to albumin
Biotransformation: Hepatic.
Half Life: Low doses: 3 to 10 hours; High doses: 8 to 15 hours.
Dosage Forms of Methotrate: Solution Intravenous
Tablet Oral
Solution Intrathecal
Solution Intramuscular
Chemical IUPAC Name: (2S)-2-[[4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]pentanedioic acid
Chemical Formula: C20H22N8O5
Methotrexate on Wikipedia: https://en.wikipedia.org/wiki/Methotrexate
Organisms Affected: Humans and other mammals