Tìm theo
Leflunomide
Các tên gọi khác (8 ) :
  • 5-Methyl-N-(4-(trifluoromethyl)phenyl)-4-isoxazolecarboxamide
  • 5-Methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide
  • alpha,alpha,alpha-Trifluoro-5-methyl-4-isoxazolecarboxy-P-toluidide
  • Arava
  • Leflunomida
  • Leflunomide
  • Leflunomidum
  • Lefunomide
Thuốc giảm đau, hạ sốt, chống viêm không steroid, điều trị Gút và các bệnh xương khớp
Thuốc Gốc
Small Molecule
CAS: 75706-12-6
ATC: L04AA13
ĐG : Apotex Inc. , http://www.apotex.com
CTHH: C12H9F3N2O2
PTK: 270.2073
Leflunomide is a pyrimidine synthesis inhibitor belonging to the DMARD (disease-modifying antirheumatic drug) class of drugs, which are chemically and pharmacologically very heterogeneous. Leflunomide was approved by FDA and in many other countries (e.g., Canada, Europe) in 1999.
Nhận Dạng Quốc Tế & Đặc Tính Hóa Học
Công thức hóa học
C12H9F3N2O2
Phân tử khối
270.2073
Monoisotopic mass
270.061612157
InChI
InChI=1S/C12H9F3N2O2/c1-7-10(6-16-19-7)11(18)17-9-4-2-8(3-5-9)12(13,14)15/h2-6H,1H3,(H,17,18)
InChI Key
InChIKey=VHOGYURTWQBHIL-UHFFFAOYSA-N
IUPAC Name
5-methyl-N-[4-(trifluoromethyl)phenyl]-1,2-oxazole-4-carboxamide
Traditional IUPAC Name
leflunomide
SMILES
CC1=C(C=NO1)C(=O)NC1=CC=C(C=C1)C(F)(F)F
Độ tan chảy
165-166 °C
Độ hòa tan
21 mg/L (poorly soluble)
logP
2.8
logS
-3.5
pKa (strongest acidic)
10.41
pKa (Strongest Basic)
-0.45
PSA
55.13 Å2
Refractivity
64.16 m3·mol-1
Polarizability
23.11 Å3
Rotatable Bond Count
3
H Bond Acceptor Count
2
H Bond Donor Count
1
Physiological Charge
0
Number of Rings
2
Bioavailability
1
Rule of Five
true
Ghose Filter
true
Dược Lực Học : 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.
Cơ Chế Tác Dụng : Leflunomide is a pyrimidine synthesis inhibitor belonging to the DMARD (disease-modifying antirheumatic drug) class of drugs, which are chemically and pharmacologically very heterogeneous. Leflunomide was approved by FDA and in many other countries (e.g., Canada, Europe) in 1999. 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.
Dược Động Học :
▧ Absorption :
Well absorbed, peak plasma concentrations appear 6-12 hours after dosing
▧ Volume of Distribution :
* 0.13 L/kg
▧ 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.
▧ Half Life :
2 weeks
Độc Tính : LD50=100-250 mg/kg (acute oral toxicity)
Chỉ Định : 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.
Tương Tác Thuốc :
  • Abatacept Therapy modification should be considered due to enhanced adverse effects of leflunomide, specifically hematologic toxicity.
  • Acenocoumarol Leflunomide may increase the anticoagulant effect of acenocoumarol.
  • Anisindione Leflunomide may increase the anticoagulant effect of anisindione.
  • Antithymocyte globulin Therapy modification may be required because the combination enhances toxic effects of leflunomide.
  • Belatacept Consider therapy modification due to enhanced adverse effects of leflunomide, especially hematologic toxicities.
  • Belimumab Consider modifying therapy as belimumab may enhance the adverse effects of leflunomide, such as hematologic toxicities.
  • Bleomycin Immunosuppressants like bleomycin may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Consider eliminating the use of a leflunomide loading dose in patients who are receiving other immunosuppressants in order to reduce the risk for serious adverse events such as hematologic toxicity.
  • Carboplatin Immunosuppressants such as carboplatin may enhance the adverse/toxic effect of leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Consider eliminating the use of a leflunomide loading dose in patients who are receiving other immunosuppressants in order to reduce the risk for serious adverse events such as hematologic toxicity. Also, patients receiving both leflunomide and another immunosuppressive medication should be monitored for bone marrow suppression at least monthly throughout the duration of concurrent therapy.
  • Carmustine Immunosuppressants such as carmustine may enhance the adverse/toxic effect of leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Consider eliminating the use of a leflunomide loading dose in patients who are receiving other immunosuppressants in order to reduce the risk for serious adverse events such as hematologic toxicity. Also, patients receiving both leflunomide and another immunosuppressive medication should be monitored for bone marrow suppression at least monthly throughout the duration of concurrent therapy.
  • Chlorambucil Immunosuppressants such as chlorambucil may enhance the adverse/toxic effect of leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Consider eliminating the use of a leflunomide loading dose in patients who are receiving other immunosuppressants in order to reduce the risk for serious adverse events such as hematologic toxicity. Also, patients receiving both leflunomide and another immunosuppressive medication should be monitored for bone marrow suppression at least monthly throughout the duration of concurrent therapy.
  • Cisplatin Immunosuppressants such as cisplatin may enhance the adverse/toxic effect of leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Consider eliminating the use of a leflunomide loading dose in patients who are receiving other immunosuppressants in order to reduce the risk for serious adverse events such as hematologic toxicity. Also, patients receiving both leflunomide and another immunosuppressive medication should be monitored for bone marrow suppression at least monthly throughout the duration of concurrent therapy.
  • Cladribine Immunosuppressants such as cladribine may enhance the adverse/toxic effect of leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Consider eliminating the use of a leflunomide loading dose in patients who are receiving other immunosuppressants in order to reduce the risk for serious adverse events such as hematologic toxicity. Also, patients receiving both leflunomide and another immunosuppressive medication should be monitored for bone marrow suppression at least monthly throughout the duration of concurrent therapy.
  • Clofarabine Immunosuppressants such as clofarabine may enhance the adverse/toxic effect of leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Consider eliminating the use of a leflunomide loading dose in patients who are receiving other immunosuppressants in order to reduce the risk for serious adverse events such as hematologic toxicity. Also, patients receiving both leflunomide and another immunosuppressive medication should be monitored for bone marrow suppression at least monthly throughout the duration of concurrent therapy.
  • Colesevelam Bile Acid Sequestrants may decrease serum concentrations of the active metabolite(s) of Leflunomide. Unless using cholestyramine (or another bile acid sequestrant) together with leflunomide to intentionally enhance the removal/elimination of leflunomide, consider using an alternative to the bile acid sequestrants whenever possible. Separating the administration of these agents is unlikely to be an effective means of avoiding the interaction.
  • Corticotropin Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Consider eliminating the use of a leflunomide loading dose in patients who are receiving other immunosuppressants in order to reduce the risk for serious adverse events such as hematologic toxicity. Also, patients receiving both leflunomide and another immunosuppressive medication should be monitored for bone marrow suppression at least monthly throughout the duration of concurrent therapy.
  • Dicoumarol Leflunomide may increase the anticoagulant effect of dicumarol.
  • Eltrombopag Affects hepatic CYP2C9/10 metabolism, will increase effect/level of eltrombopag.
  • Etanercept Consider modifying therapy due to enhanced adverse effects of leflunomide including hematologic toxicity.
  • Gemtuzumab ozogamicin Consider modifying therapy due to adverse effects of leflunomide including the risk of hematologic toxicity.
  • Glatiramer Acetate Consider therapy modification due to enhanced adverse effects of leflunomide including hematologic toxicity.
  • Ibritumomab May need to modify therapy to avoid adverse effects of leflunomide such as hematologic toxicity.
  • Infliximab Therapy modification should be considered in order to reduce the risk of hematologic toxicities.
  • Obinutuzumab Consider modifying therapy. Risk of hematologic toxicity of leflunomide may be increased due to enhanced adverse effects.
  • Omalizumab Consider modifying therapy due to increased adverse effects of leflunomide including hematological toxicity.
  • Pegaspargase Immunosuppressants can increase toxic effects of leflunomide such as hematologic toxicity.
  • Rifampicin Rifampin increases the effect of leflunomide
  • Rilonacept results in increased immunosuppressive effects; increases the risk of infection.
  • Teriflunomide Avoid combination due to increased adverse effects of teriflunomide.
  • Tofacitinib Leflunomide may experience an increase in toxicity and adverse effects (ie. pancytopenia, agranulocytosis, thrombocytopenia). It is recommended to adjust therapy by forgoing a leflunomide loading dose, and to monitor for bone marrow suppression monthly.
  • Vinblastine Vinblastine may increase the adverse/toxic effects of Leflunomide. This may increase the risk of hematologic toxicities such as pancytopenia, agranulocytosis and thrombocytopenia. In patients receiving Vinblastine, consider eliminating the loading dose of Leflunomide. Monitor for bone marrow suppression at least monthly during concomitant therapy.
  • Vincristine Vincristine may increase the adverse/toxic effects of Leflunomide. This may increase the risk of hematologic toxicities such as pancytopenia, agranulocytosis and thrombocytopenia. In patients receiving Vincristine, consider eliminating the loading dose of Leflunomide. Monitor for bone marrow suppression at least monthly during concomitant therapy.
  • Vinorelbine Vinorelbine may increase the adverse/toxic effects of Leflunomide. This may increase the risk of hematologic toxicities such as pancytopenia, agranulocytosis and thrombocytopenia. In patients receiving Vinorelbine, consider eliminating the loading dose of Leflunomide. Monitor for bone marrow suppression at least monthly during concomitant therapy.
  • Warfarin Leflunomide may increase the anticoagulant effect of warfarin.
Liều Lượng & Cách Dùng : Tablet - Oral
Dữ Kiện Thương Mại
Giá thị trường
  • Biệt dược thương mại : Leflunomide 10 mg tablet
    Giá bán buôn : USD >16.75
    Đơn vị tính : tablet
  • Biệt dược thương mại : Leflunomide 20 mg tablet
    Giá bán buôn : USD >16.75
    Đơn vị tính : tablet
  • Biệt dược thương mại : Arava 10 mg tablet
    Giá bán buôn : USD >24.76
    Đơn vị tính : tablet
  • Biệt dược thương mại : Arava 20 mg tablet
    Giá bán buôn : USD >24.76
    Đơn vị tính : tablet
Nhà Sản Xuất
  • Công ty :
    Sản phẩm biệt dược : Arava
Đóng gói
Tài Liệu Tham Khảo Thêm
drugbank
http://www.drugbank.ca/drugs/DB01097
PubChem Compound
http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=3899
PubChem Substance
http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=46506013
KEGG Compound
http://www.genome.jp/dbget-bin/www_bget?cpd:C07905
KEGG Drug
http://www.genome.jp/dbget-bin/www_bget?drug:D00749
ChemSpider
http://www.chemspider.com/Chemical-Structure.3762.html
National Drug Code Directory
http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/0555-0351-01
PharmGKB
http://www.pharmgkb.org/drug/PA450192
Wikipedia
http://en.wikipedia.org/wiki/Leflunomide
RxList
http://www.rxlist.com/cgi/generic3/leflunomide.htm
Drugs.com
http://www.drugs.com/cdi/leflunomide.html
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