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Methotrexate | CAS No: 59-05-2 | GMP-certified suppliers
A medication that treats leukemias and other cancers, relieves severe inflammatory joint diseases, and supports systemic management of moderate‑to‑severe psoriasis across key clinical settings.
Therapeutic categories
Abortifacient AgentsAbortifacient Agents, NonsteroidalAgents Causing Muscle ToxicityAntimetabolitesAntineoplastic AgentsAntineoplastic and Immunomodulating Agents
Generic name
Methotrexate
Molecule type
small molecule
CAS number
59-05-2
DrugBank ID
DB00563
Approval status
Approved drug
ATC code
L04AX03
Primary indications
- Methotrexate oral solution is indicated for pediatric acute lymphoblastic leukemia and pediatric polyarticular juvenile idiopathic arthritis
- Methotrexate injections for subcutaneous use are indicated for severe active rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and severe, recalcitrant, disabling psoriasis
- It has also been approved by the EMA for the treatment of adult patients requiring systemic therapy for moderate-to-severe plaque psoriasis
Product Snapshot
- Methotrexate is available as an oral small‑molecule solution or tablet and as multiple parenteral formulations including injectable solutions and lyophilized powders
- It is used across oncology and immunology for acute lymphoblastic leukemia, juvenile idiopathic arthritis, rheumatoid arthritis, psoriasis, and various solid and hematologic malignancies
- It is an approved product in the US, EU, and Canada
Clinical Overview
Methotrexate (CAS 59-05-2) is a folate analogue classified among glutamic acid derivatives. It inhibits multiple folate‑dependent enzymes required for de novo nucleotide synthesis, producing antiproliferative and immunomodulatory effects. Clinically, it is used across oncology, rheumatology, and dermatology settings. Key indications include pediatric acute lymphoblastic leukemia, maintenance therapy in acute lymphocytic leukemia, polyarticular juvenile idiopathic arthritis, severe active rheumatoid arthritis, and severe psoriasis requiring systemic therapy. Additional oncologic applications include gestational trophoblastic disease, breast cancer, head and neck cancer, mycosis fungoides, lung cancer, advanced non‑Hodgkin’s lymphoma, and perioperative treatment of non‑metastatic osteosarcoma when followed by leucovorin rescue.
Methotrexate exerts its pharmacological effect after intracellular conversion to methotrexate polyglutamates. These metabolites inhibit dihydrofolate reductase, thymidylate synthase, AICART, and amido phosphoribosyltransferase, causing interruption of DNA synthesis and cell division. In inflammatory disease, enhanced inhibition of AICART increases extracellular adenosine concentrations, mediating anti‑inflammatory activity. The drug has a long duration of action and is typically administered weekly due to its narrow therapeutic index.
Absorption and disposition parameters vary with formulation and route. Methotrexate is handled by several hepatic and renal transporters, including OAT, OATP, BCRP, and P‑glycoprotein. Renal elimination is a major clearance pathway, and impaired renal function increases systemic exposure. Drug interactions with transporter modulators or nephrotoxic agents can significantly alter levels.
Toxicity concerns include myelosuppression, hepatotoxicity, nephrotoxicity, mucosal injury, and photosensitivity. Risk is elevated with dosing errors, particularly inadvertent daily administration. Concomitant drugs affecting folate pathways or renal excretion require careful monitoring.
Notable product contexts include oral solutions for pediatric leukemia and JIA, and subcutaneous formulations for arthritis and psoriasis.
For API procurement, manufacturers should verify compliance with pharmacopeial specifications, ensure controlled impurity profiles, and confirm suitability for finished dosage formulations requiring tight dose accuracy due to the narrow therapeutic index.
Methotrexate exerts its pharmacological effect after intracellular conversion to methotrexate polyglutamates. These metabolites inhibit dihydrofolate reductase, thymidylate synthase, AICART, and amido phosphoribosyltransferase, causing interruption of DNA synthesis and cell division. In inflammatory disease, enhanced inhibition of AICART increases extracellular adenosine concentrations, mediating anti‑inflammatory activity. The drug has a long duration of action and is typically administered weekly due to its narrow therapeutic index.
Absorption and disposition parameters vary with formulation and route. Methotrexate is handled by several hepatic and renal transporters, including OAT, OATP, BCRP, and P‑glycoprotein. Renal elimination is a major clearance pathway, and impaired renal function increases systemic exposure. Drug interactions with transporter modulators or nephrotoxic agents can significantly alter levels.
Toxicity concerns include myelosuppression, hepatotoxicity, nephrotoxicity, mucosal injury, and photosensitivity. Risk is elevated with dosing errors, particularly inadvertent daily administration. Concomitant drugs affecting folate pathways or renal excretion require careful monitoring.
Notable product contexts include oral solutions for pediatric leukemia and JIA, and subcutaneous formulations for arthritis and psoriasis.
For API procurement, manufacturers should verify compliance with pharmacopeial specifications, ensure controlled impurity profiles, and confirm suitability for finished dosage formulations requiring tight dose accuracy due to the narrow therapeutic index.
Identification & chemistry
| Generic name | Methotrexate |
|---|---|
| Molecule type | Small molecule |
| CAS | 59-05-2 |
| UNII | YL5FZ2Y5U1 |
| DrugBank ID | DB00563 |
Pharmacology
| Summary | Methotrexate is an antifolate agent that is intracellularly converted to polyglutamated forms that inhibit key enzymes in nucleotide synthesis, including dihydrofolate reductase, thymidylate synthase, and AICART. These actions suppress cellular proliferation in malignant cells and modulate immune activity through downstream adenosine accumulation. Its pharmacodynamic profile reflects targeted disruption of folate‑dependent metabolic pathways that drive both cytotoxic and anti‑inflammatory effects. |
|---|---|
| Mechanism of action | Methotrexate enters tissues and is converted to a methotrexate polyglutamate by folylpolyglutamate. Methotrexate's mechanism of action is due to its inhibition of enzymes responsible for nucleotide synthesis including dihydrofolate reductase, thymidylate synthase, aminoimidazole caboxamide ribonucleotide transformylase (AICART), and amido phosphoribosyltransferase.Inhibtion of nucleotide synthesis prevents cell division. In rheumatoid arthritis, methotrexate polyglutamates inhibit AICART more than methotrexate.This inhibition leads to accumulation of AICART ribonucleotide, which inhibits adenosine deaminase, leading to an accumulation of adenosine triphosphate and adenosine in the extracellular space, stimulating adenosine receptors, leading to anti-inflammatory action. |
| Pharmacodynamics | Methotrexate inhibits enzymes responsible for nucleotide synthesis which prevents cell division and leads to anti-inflammatory actions.It has a long duration of action and is generally given to patients once weekly.Methotrexate has a narrow therapeutic index. Do not take methotrexate daily. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Thymidylate synthase | Humans | inhibitor |
| Bifunctional purine biosynthesis protein PURH | Humans | inhibitor |
| Dihydrofolate reductase | Humans | inhibitor |
ADME / PK
| Absorption | Methotrexate has a bioavailability of 64-90%, though this decreases at oral doses above 25mg due to saturation of the carrier mediated transport of methotrexate.. Methotrexate has a T<sub>max</sub> of 1 to 2 hours.oral doses of 10-15µg reach serum levels of 0.01-0.1µM. |
|---|---|
| Half-life | The half life of low dose methotrexate is 3 to 10 hours in adults.The half life for high dose methotrexate is 8 to 15 hours.Pediatric patients taking methotrexate for acute lymphoblastic anemia experience a terminal half life of 0.7 to 5.8 hours.Pediatric patients taking methotrexate for juvenile idiopathic arthritis experience a half life of 0.9 to 2.3 hours. |
| Protein binding | Methotrexate is 46.5-54% bound to plasma proteins. |
| Metabolism | Methotrexate is metabolized by folylpolyglutamate synthase to methotrexate polyglutamate in the liver as well as in tissues.Gamma-glutamyl hydrolase hydrolyzes the glutamyl chains of methotrexate polyglutamates converting them back to methotrexate.A small amount of methotrexate is also converted to 7-hydroxymethotrexate. |
| Route of elimination | Methotrexate is >80% excreted as the unchanged drug and approximately 3% as the 7-hydroxylated metabolite.Methotrexate is primarily excreted in the urine with 8.7-26% of an intravenous dose appearing in the bile. |
| Volume of distribution | The volume of distribution of methotrexate at steady state is approximately 1L/kg. |
| Clearance | Methotrexate clearance varies widely between patients and decreases with increasing doses.Currently, predicting clearance of methotrexate is difficult and exceedingly high serum levels of methotrexate can still occur when all precautions are taken. |
Formulation & handling
- Parenteral and oral options are available, with injectable forms often used at higher concentrations or for intrathecal and intra‑arterial administration requiring strict sterility and pH/osmolality control.
- Low aqueous solubility may necessitate pH adjustment or solubilizing excipients for concentrated solutions, and lyophilized powders require careful reconstitution to avoid precipitation.
- Oral formulations can exhibit food‑related absorption variability, and dairy products can reduce uptake, which may influence bioavailability targets during product development.
Regulatory status
| Lifecycle | The API remains partially protected in the United States until 2030, while earlier‑expiring patents suggest some aspects may already face reduced exclusivity. With products marketed in the US, Canada, and the EU, the asset is positioned in a mature multiregional market approaching its final phase of U.S. patent protection. |
|---|
| Markets | Canada, US, EU |
|---|
Supply Chain
| Supply chain summary | Methotrexate has long-established manufacturing with many generic producers—ranging from legacy originator entities to a broad set of U.S. and international manufacturers—and an extensive network of repackagers supporting distribution. Branded and generic products are widely available across the US, EU, and Canada. Core compound patents have expired, and the remaining U.S. patents appear to relate to specific formulations, indicating that broad generic competition is already well established. |
|---|
Safety
| Toxicity | The oral LD<sub>50</sub> in rats is 135mg/kg and in mice is 146mg/kg. Symptoms of overdose include hematologic and gastrointestinal reactions like leukopenia, thombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, and gastrointestinal bleeding.In the event of an overdose, patients should be treated with glucarpidase and not be given leucovorin for 2 hours before or after glucarpidase. |
|---|
High Level Warnings:
- Exhibits high acute oral toxicity (rat LD50 ~135 mg/kg
- Mouse LD50 ~146 mg/kg), warranting controlled handling and exposure minimization in manufacturing environments
- Associated with severe hematologic and gastrointestinal toxicities, including leukopenia, thrombocytopenia, pancytopenia, and mucosal injury, indicating a need for robust containment and monitoring of occupational exposure
US Drug Master File (USDMF)
A US Drug Master File (USDMF) is a confidential document submitted to the U.S. Food and Drug Administration (FDA) that provides detailed information about the manufacturing process of an Active Pharmaceutical Ingredient (API) or a finished pharmaceutical product. This document includes comprehensive details such as chemical properties, manufacturing facilities, production processes, packaging specifications, storage conditions, and more.
The USDMF ensures that proprietary information remains protected while allowing the FDA to review the data as part of drug approval processes. Unlike other types of DMFs used in different regions, the USDMF is specifically designed to meet the regulatory requirements set by the FDA, ensuring compliance with U.S. standards.
Methotrexate is a type of Antimetabolites
Antimetabolites are a prominent category of pharmaceutical active pharmaceutical ingredients (APIs) utilized in the treatment of various diseases, particularly cancer. These compounds are structurally similar to naturally occurring metabolites essential for cellular processes such as DNA and RNA synthesis. By mimicking these metabolites, antimetabolites interfere with the normal functioning of cellular pathways, leading to inhibition of cancer cell growth and proliferation.
One of the widely used antimetabolites is methotrexate, a folic acid antagonist that inhibits the enzyme dihydrofolate reductase, disrupting the production of DNA and RNA. This disruption impedes the growth of rapidly dividing cancer cells. Another common antimetabolite is 5-fluorouracil (5-FU), which inhibits the enzyme thymidylate synthase, thereby interfering with DNA synthesis and inhibiting cancer cell proliferation.
Antimetabolites can be classified into several subcategories based on their mechanism of action and chemical structure. These include purine and pyrimidine analogs, folic acid antagonists, and pyrimidine synthesis inhibitors. Examples of antimetabolites in these subcategories include azathioprine, cytarabine, and gemcitabine.
Despite their effectiveness, antimetabolites can exhibit certain side effects due to their interference with normal cellular processes. These side effects may include gastrointestinal disturbances, myelosuppression (reduced production of blood cells), and hepatotoxicity.
In conclusion, antimetabolites are a vital category of pharmaceutical APIs used in the treatment of various diseases, especially cancer. By mimicking natural metabolites and disrupting crucial cellular processes, these compounds effectively inhibit cancer cell growth and proliferation. However, their usage should be carefully monitored due to potential side effects.
Methotrexate API manufacturers & distributors
Compare qualified Methotrexate API suppliers worldwide. We currently have 10 companies offering Methotrexate API, with manufacturing taking place in 5 different countries. Use the table below to review supplier type, countries of origin, certifications, product portfolio and GMP audit availability.
| Supplier | Type | Country | Product origin | Certifications | Portfolio |
|---|---|---|---|---|---|
| CF Pharma | Producer | Hungary | Hungary | CEP, CoA, FDA, GMP, USDMF | 7 products |
| Fermion | Producer | Finland | Finland | BSE/TSE, CEP, CoA, GDP, GMP, JDMF, Other, MSDS, USDMF | 29 products |
| Mac Chem Products | Producer | India | India | CoA, GMP, WC | 25 products |
| Patriapharma | Producer | Hungary | Hungary | CoA | 1 products |
| Rochem International, Inc... | Distributor | United States | United States | BSE/TSE, CEP, CoA, GMP, ISO9001, MSDS, USDMF | 144 products |
| SETV Global | Producer | India | India | CoA, FDA, GMP | 515 products |
| Shanghai Jinhe Bio-Pharma | Producer | China | China | CoA | 12 products |
| Suryakala Laboratories Pv... | Producer | India | India | CoA, ISO9001 | 6 products |
| Zhejiang Haizhou | Producer | China | China | CoA, WC | 3 products |
| Zhejiang Hisun Pharma | Producer | China | China | CEP, CoA, GMP, USDMF, WC | 69 products |
When sending a request, specify which Methotrexate API quality you need: for example EP (Ph. Eur.), USP, JP, BP, or another pharmacopoeial standard, as well as the required grade (base, salt, micronised, specific purity, etc.).
Use the list above to find high-quality Methotrexate API suppliers. For example, you can select GMP, FDA or ISO certified suppliers. Visit our help page to learn more about sourcing APIs via Pharmaoffer.
Frequently asked questions about Methotrexate API
Sourcing
What matters most when sourcing GMP-grade Methotrexate?
Key considerations include confirming GMP compliance and alignment with regulatory expectations in the US, EU, and Canada. Suppliers should have a documented quality system, consistent batch-to-batch performance, and clear traceability through any repackagers. Given broad generic competition, assessing regulatory history and supply reliability is essential.
Which documents are typically required when sourcing Methotrexate API?
Request the core API documentation set: CoA (10 companies), GMP (6 companies), CEP (4 companies), USDMF (4 companies), WC (3 companies). Confirm versions and validity dates match the destination market to avoid delays in qualification.
Which manufacturers are known to produce Methotrexate API?
Known or reported manufacturers for Methotrexate: SETV Global, Rochem International, Inc.. Evaluate their GMP history, scale, and regional coverage before requesting dossiers or allocating demand.
How can I request quotes for Methotrexate API from GMP suppliers?
Submit quote requests through the supplier listings with your specs and required documents (specifications, target volume, delivery timeline, and destination). Providing consistent details upfront speeds comparable offers and clarifies technical feasibility.
Is a GMP audit report available for Methotrexate manufacturers?
Audit reports may be requested for Methotrexate: 3 GMP audit reports available. Confirm the scope and recency of any audit before relying on it for qualification decisions.
How many suppliers offer Methotrexate API on Pharmaoffer?
Reported supplier count for Methotrexate: 10 verified suppliers. Filter listings by certifications, regions, and delivery options to match your qualification plan.
Which countries are known to manufacture Methotrexate API?
Production countries reported for Methotrexate: India (3 producers), China (3 producers), Hungary (2 producers). Knowing the manufacturing geography helps anticipate logistics lead times and import compliance needs.
Which certifications do suppliers of Methotrexate usually hold?
Common certifications for Methotrexate suppliers: CoA (10 companies), GMP (6 companies), CEP (4 companies), USDMF (4 companies), WC (3 companies). Always verify issuing authorities and expiry dates when reviewing audit packages.
Technical
What is Methotrexate (CAS 59-05-2) used for?
Methotrexate is used to treat cancers and immune‑mediated diseases due to its inhibition of folate‑dependent enzymes needed for nucleotide synthesis. It is indicated for pediatric and adult acute lymphoblastic leukemia, multiple solid tumors, gestational trophoblastic disease, non‑Hodgkin’s lymphoma, and perioperative treatment of non‑metastatic osteosarcoma with leucovorin rescue. In rheumatology and dermatology, it is used for severe rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, and severe psoriasis requiring systemic therapy.
Which therapeutic class does Methotrexate fall into?
Methotrexate belongs to the following therapeutic categories: Abortifacient Agents, Abortifacient Agents, Nonsteroidal, Agents Causing Muscle Toxicity, Antimetabolites, Antineoplastic Agents. This positioning helps teams compare alternative APIs, anticipate pharmacology expectations, and align early research priorities.
What conditions is Methotrexate mainly prescribed for?
The primary indications for Methotrexate: Methotrexate oral solution is indicated for pediatric acute lymphoblastic leukemia and pediatric polyarticular juvenile idiopathic arthritis, Methotrexate injections for subcutaneous use are indicated for severe active rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and severe, recalcitrant, disabling psoriasis, It has also been approved by the EMA for the treatment of adult patients requiring systemic therapy for moderate-to-severe plaque psoriasis. These use cases frame the target patient populations and help prioritize formulation and safety evaluations.
How does Methotrexate work?
Methotrexate enters tissues and is converted to a Methotrexate polyglutamate by folylpolyglutamate.
Methotrexate's mechanism of action is due to its inhibition of enzymes responsible for nucleotide synthesis including dihydrofolate reductase, thymidylate synthase, aminoimidazole caboxamide ribonucleotide transformylase (AICART), and amido phosphoribosyltransferase.Inhibtion of nucleotide synthesis prevents cell division.
In rheumatoid arthritis, Methotrexate polyglutamates inhibit AICART more than Methotrexate.This inhibition leads to accumulation of AICART ribonucleotide, which inhibits adenosine deaminase, leading to an accumulation of adenosine triphosphate and adenosine in the extracellular space, stimulating adenosine receptors, leading to anti-inflammatory action.
What should someone know about the safety or toxicity profile of Methotrexate?
Methotrexate has a narrow therapeutic index and can produce severe hematologic, gastrointestinal, hepatic, and renal toxicities. It shows high acute oral toxicity in animal studies and requires strict controls to limit occupational exposure during manufacturing. Clinically, major risks include myelosuppression, mucosal injury, hepatotoxicity, nephrotoxicity, and photosensitivity, with increased danger from dosing errors or impaired renal function. Interactions with drugs affecting folate pathways or renal transport can raise systemic levels and require close monitoring.
What are important formulation and handling considerations for Methotrexate as an API?
Important considerations include managing Methotrexate’s low aqueous solubility, which may require pH adjustment or solubilizing excipients, especially for concentrated solutions or lyophilized products to prevent precipitation during reconstitution. Parenteral preparations must maintain strict sterility and appropriate pH and osmolality, particularly for intrathecal or intra‑arterial use. Oral formulations should account for food‑related absorption variability, including reduced uptake with dairy products.
Is Methotrexate a small molecule?
Methotrexate is classified as a small molecule. That classification shapes process design, impurity profiling, and analytical control strategies.
Are there special stability concerns for oral Methotrexate?
Oral Methotrexate has low aqueous solubility, so formulation strategies may require pH adjustment or solubilizing excipients to prevent precipitation in more concentrated preparations. Its absorption can vary with food intake, and dairy products can reduce uptake, which may influence how the oral dosage form maintains consistent performance. No additional stability issues are noted in the provided context.
Regulatory
Where is Methotrexate approved or in use globally?
Methotrexate is reported as approved in the following major regions: Canada, US, EU. Understanding geographic coverage informs regulatory filings, supply planning, and risk assessments before escalating procurement.
Pharmaoffer
How does Pharmaoffer’s Smart Sourcing Service help with Methotrexate procurement?
Pharmaoffer's Smart Sourcing Service coordinates compliant suppliers, documentation, and competitive quotes for Methotrexate. It centralizes outreach, follow-ups, and document validation to shorten procurement timelines.
Is Methotrexate included in the PRO Data Insights coverage?
PRO Data Insights coverage for Methotrexate: 1103 verified transactions across 221 suppliers and 198 buyers worldwide. Use the dataset to benchmark suppliers and monitor regulatory activity where available.
Where can I access the API market report for Methotrexate?
Market report availability for Methotrexate: Report Available. The report highlights demand trends, pricing drivers, and supplier landscape insights for procurement planning.
