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Leflunomide | CAS No: 75706-12-6 | GMP-certified suppliers
A medication that manages active rheumatoid arthritis by improving symptoms and function and is also used to support prevention of rejection in solid organ transplantation.
Therapeutic categories
Primary indications
- For the management of the signs and symptoms of active rheumatoid arthritis (RA) to improve physical function and to slow the progression of structural damage associated with the disease
- Has also been used for the prevention of acute and chronic rejection in recipients of solid organ trasnplants and is designated by the FDA as an orphan drug for this use
Product Snapshot
- Leflunomide is an oral small‑molecule agent available mainly as tablets and capsules, with some topical formulations
- It is used for rheumatoid arthritis and has additional utility in transplant rejection settings under orphan drug designation
- It is approved in the US, EU, and Canada, with some investigational status in certain markets
Clinical Overview
Following oral administration, leflunomide is rapidly converted to its active metabolite A77 1726, which accounts for its pharmacological activity. The compound modulates immune responses by inhibiting de novo pyrimidine synthesis through blockade of dihydroorotate dehydrogenase. Activated T lymphocytes rely on this pathway to meet the heightened nucleotide demand required for proliferation. Inhibition reduces uridine monophosphate formation, leading to decreased DNA and RNA synthesis, cell cycle arrest in G1, and suppression of T‑cell expansion. B‑cell autoantibody production and adhesion of activated lymphocytes to synovial endothelium are also reduced. A77 1726 additionally inhibits certain tyrosine kinases, contributing to its antiproliferative effects.
Leflunomide demonstrates high oral bioavailability with extensive plasma protein binding and a long elimination half‑life driven by enterohepatic recirculation. Metabolism occurs primarily via non‑enzymatic and hepatic pathways, and excretion involves both fecal and renal routes. Steady‑state levels may take weeks to achieve without loading doses.
Safety considerations include hepatotoxicity, teratogenicity, cytopenias, and gastrointestinal and dermatologic reactions. Because of its long half‑life, cholestyramine washout procedures may be required in cases of toxicity or pregnancy planning. Drug–drug interactions may occur with CYP2C9 substrates, and the compound is also a substrate of ABCG2.
Leflunomide is available globally in branded and generic formulations, with Arava being the most widely recognized brand. For API procurement, suppliers should demonstrate control of isoxazole‑related impurities, verification of stereochemical identity of the active metabolite precursor, and adherence to current regulatory specifications and residual solvent limits.
Identification & chemistry
| Generic name | Leflunomide |
|---|---|
| Molecule type | Small molecule |
| CAS | 75706-12-6 |
| UNII | G162GK9U4W |
| DrugBank ID | DB01097 |
Pharmacology
| Summary | Leflunomide is a prodrug converted to the active metabolite A77 1726, which modulates immune activity primarily by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase, a key catalyst in de novo pyrimidine synthesis. This inhibition limits nucleotide availability in activated lymphocytes, leading to reduced proliferation and downstream effects such as altered cytokine signaling and impaired cell‑cycle progression. A77 1726 also interacts with additional targets, including tyrosine kinases and the aryl hydrocarbon receptor, contributing to its broader immunomodulatory profile. |
|---|---|
| Mechanism of action | Leflunomide is a prodrug that is rapidly and almost completely metabolized following oral administration to its pharmacologically active metabolite, A77 1726. This metabolite is responsible for essentially all of the drug's activity in-vivo. The mechanism of action of leflunomide has not been fully determined, but appears to primarily involve regulation of autoimmune lymphocytes. It has been suggested that leflunomide exerts its immunomodulating effects by preventing the expansion of activated autoimmune lymphocytes via interferences with cell cycle progression. In-vitro data indicates that leflunomide interferes with cell cycle progression by inhibiting dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine ribonucleotide uridine monophosphate (rUMP)synthesis) and has antiproliferative activity. Human dihydroorotate dehydrogenase consists of 2 domains: an α/β-barrel domain containing the active site and an α-helical domain that forms a tunnel leading to the active site. A77 1726 binds to the hydrophobic tunnel at a site near the flavin mononucleotide. Inhibition of dihydroorotate dehydrogenase by A77 1726 prevents production of rUMP by the de novo pathway; such inhibition leads to decreased rUMP levels, decreased DNA and RNA synthesis, inhibition of cell proliferation, and G1 cell cycle arrest. It is through this action that leflunomide inhibits autoimmune T-cell proliferation and production of autoantibodies by B cells. Since salvage pathways are expected to sustain cells arrested in the G1 phase, the activity of leflunomide is cytostatic rather than cytotoxic. Other effects that result from reduced rUMP levels include interference with adhesion of activated lymphocytes to the synovial vascular endothelial cells, and increased synthesis of immunosuppressive cytokines such as transforming growth factor-β (TGF-β). Leflunomide is also a tyrosine kinase inhibitor. Tyrosine kinases activate signalling pathways leading to DNA repair, apoptosis and cell proliferation. Inhibition of tyrosine kinases can help to treating cancer by preventing repair of tumor cells. |
| Pharmacodynamics | Leflunomide is a pyrimidine synthesis inhibitor indicated in adults for the treatment of active rheumatoid arthritis (RA). RA is an auto-immune disease characterized by high T-cell activity. T cells have two pathways to synthesize pyrimidines: the salvage pathways and the de novo synthesis. At rest, T lymphocytes meet their metabolic requirements by the salvage pathway. Activated lymphocytes need to expand their pyrimidine pool 7- to 8-fold, while the purine pool is expanded only 2- to 3-fold. To meet the need for more pyrimidines, activated T cells use the de novo pathway for pyrimidine synthesis. Therefore, activated T cells, which are dependent on de novo pyrimidine synthesis, will be more affected by leflunomide's inhibition of dihydroorotate dehydrogenase than other cell types that use the salvage pathway of pyrimidine synthesis. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Dihydroorotate dehydrogenase (quinone), mitochondrial | Humans | inhibitor |
| Aryl hydrocarbon receptor | Humans | agonist |
| Protein-tyrosine kinase 2-beta | Humans | antagonist |
ADME / PK
| Absorption | Well absorbed, peak plasma concentrations appear 6-12 hours after dosing |
|---|---|
| Half-life | 2 weeks |
| Protein binding | >99.3% |
| Metabolism | Primarily hepatic. Leflunomide is converted to its active form following oral intake. |
| Route of elimination | The active metabolite is eliminated by further metabolism and subsequent renal excretion as well as by direct biliary excretion. In a 28 day study of drug elimination (n=3) using a single dose of radiolabeled compound, approximately 43% of the total radioactivity was eliminated in the urine and 48% was eliminated in the feces. It is not known whether leflunomide is excreted in human milk. Many drugs are excreted in human milk, and there is a potential for serious adverse reactions in nursing infants from leflunomide. |
| Volume of distribution | * 0.13 L/kg |
Formulation & handling
- Oral small‑molecule API with food‑independent absorption, allowing flexible administration without impact on uptake.
- Low aqueous solubility may require solubility‑enhancing excipients or solid‑state optimization to ensure consistent tablet or capsule performance.
- Chemically stable aromatic anilide solid suitable for conventional oral solid‑dose processing, with standard handling for hydrophobic small molecules.
Regulatory status
| Lifecycle | I can draft the summary, but I need the patent‑expiry timing (or basic status such as “patents expired,” “expiring in 2027,” etc.). Please provide the patent‑expiry information for the API. |
|---|
| Markets | Canada, US, EU |
|---|
Supply Chain
| Supply chain summary | Leflunomide is associated with a single originator brand, with numerous packagers and generic suppliers now active, indicating a mature post‑patent market. Branded and generic products are available across the US, EU, and Canada, reflecting broad global distribution. Patent expiry has already enabled extensive generic competition. |
|---|
Safety
| Toxicity | LD<sub>50</sub>=100-250 mg/kg (acute oral toxicity) |
|---|
- Exhibits moderate acute oral toxicity (LD50 100–250 mg/kg), warranting controlled handling to limit ingestion and aerosol exposure
- Immunosuppressive activity may pose risks of occupational immune modulation
- Avoid inadvertent dermal or mucosal contact
Leflunomide is a type of Immunosuppressants
Immunosuppressants are a vital subcategory of pharmaceutical active pharmaceutical ingredients (APIs) that play a crucial role in medical treatments. These substances are designed to suppress or weaken the immune system's response, making them invaluable in various therapeutic applications.
Immunosuppressants find extensive use in the management of autoimmune diseases, organ transplantation, and the prevention of rejection reactions. By modulating the immune system's activity, these APIs help control excessive immune responses that can lead to tissue damage and chronic inflammation.
There are different classes of immunosuppressants, including corticosteroids, calcineurin inhibitors, antimetabolites, and biologics. Each class targets specific immune pathways to achieve the desired therapeutic effect. Corticosteroids, for instance, are known for their potent anti-inflammatory properties, making them effective in managing conditions such as rheumatoid arthritis and asthma.
Calcineurin inhibitors like cyclosporine and tacrolimus act by inhibiting the activity of calcineurin, a protein involved in immune cell activation. These drugs are commonly used in organ transplantation to prevent the immune system from attacking the transplanted organ.
Antimetabolites interfere with DNA synthesis and cell proliferation, thereby dampening immune responses. They are often prescribed for conditions like psoriasis and rheumatoid arthritis.
Biologic immunosuppressants, such as monoclonal antibodies, target specific immune cells or molecules involved in the disease process. They have revolutionized the treatment of autoimmune diseases like rheumatoid arthritis, Crohn's disease, and psoriasis.
Immunosuppressants require careful administration and monitoring due to their potential side effects and interactions with other medications. Close collaboration between healthcare professionals, pharmacists, and patients is essential to ensure the safe and effective use of these APIs in various therapeutic settings.
Overall, immunosuppressants represent a critical category of pharmaceutical APIs that significantly contribute to improving patients' quality of life by controlling the immune system's activity and managing various autoimmune conditions and transplantation outcomes.
Leflunomide (Immunosuppressants), classified under Immunomodulators
Immunomodulators, a category of pharmaceutical active pharmaceutical ingredients (APIs), are substances that help regulate and modify the immune response of an individual. These compounds play a crucial role in treating various immune-related disorders and diseases. Immunomodulators work by either enhancing or suppressing the immune system, depending on the specific condition being treated.
Immunomodulators are used in the treatment of autoimmune disorders, such as rheumatoid arthritis, multiple sclerosis, and psoriasis. By suppressing the immune system, these APIs help reduce the overactive immune response associated with these conditions, thereby alleviating symptoms and preventing further damage to the body's tissues.
On the other hand, immunomodulators are also employed to boost the immune system in cases of immunodeficiency disorders. These APIs stimulate the immune response, enabling the body to better fight off infections and diseases. Additionally, immunomodulators are utilized in the prevention and treatment of organ transplant rejection, where they help modulate the immune system to accept the transplanted organ.
The development and production of immunomodulators require rigorous testing and quality control to ensure their safety and efficacy. Pharmaceutical companies carefully formulate these APIs into various dosage forms, including tablets, capsules, injections, and topical preparations, to cater to different patient needs.
In summary, immunomodulators form a vital category of pharmaceutical APIs that regulate and modify the immune system. With their ability to modulate immune responses, these compounds contribute significantly to the management and treatment of various immune-related disorders and diseases, improving the quality of life for many patients.
Leflunomide API manufacturers & distributors
Compare qualified Leflunomide API suppliers worldwide. We currently have 9 companies offering Leflunomide API, with manufacturing taking place in 6 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 |
|---|---|---|---|---|---|
| Acura Labs | Producer | India | India | CoA, GMP | 18 products |
| AXXO GmbH | Distributor | Germany | World | CoA, GMP, GDP, MSDS, USDMF | 243 products |
| Cipla | Producer | India | India | CEP, CoA, FDA, GMP, USDMF, WC | 164 products |
| Emcure Pharma | Producer | India | India | CoA, USDMF | 80 products |
| Formosa Labs | Producer | Taiwan | Taiwan | CEP, CoA, FDA, GMP, USDMF | 36 products |
| Maprimed | Producer | Argentina | Argentina | CoA, USDMF | 6 products |
| Nanjing Hemu Haohai Biote... | Producer | China | China | BSE/TSE, CoA, EDMF/ASMF, MSDS, USDMF | 23 products |
| Sanofi | Producer | France | France | CoA, GMP | 93 products |
| Triquim | Producer | Argentina | Argentina | CoA, GMP, ISO9001 | 16 products |
When sending a request, specify which Leflunomide 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 Leflunomide 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.
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