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Namespace Prefixes

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Statements

Subject Item
n2:DB01097
rdf:type
n3:Drug
n3:description
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.
n3:dosage
n5:271B3E80-363D-11E5-9242-09173F13E4C5 n5:271B3E81-363D-11E5-9242-09173F13E4C5 n5:271B3E82-363D-11E5-9242-09173F13E4C5 n5:271B3E83-363D-11E5-9242-09173F13E4C5 n5:271B3E84-363D-11E5-9242-09173F13E4C5
n3:generalReferences
# Goldenberg MM: Leflunomide, a novel immunomodulator for the treatment of active rheumatoid arthritis. Clin Ther. 1999 Nov;21(11):1837-52; discussion 1821. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/10890256 # Li EK, Tam LS, Tomlinson B: Leflunomide in the treatment of rheumatoid arthritis. Clin Ther. 2004 Apr;26(4):447-59. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/15189743 # Sanders S, Harisdangkul V: Leflunomide for the treatment of rheumatoid arthritis and autoimmunity. Am J Med Sci. 2002 Apr;323(4):190-3. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/12003373 # Breedveld FC, Dayer JM: Leflunomide: mode of action in the treatment of rheumatoid arthritis. Ann Rheum Dis. 2000 Nov;59(11):841-9. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/11053058\# Reitzik M, Lownie JF: Familial polyostotic fibrous dysplasia. Oral Surg Oral Med Oral Pathol. 1975 Dec;40(6):769-74. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/1060033 # Herrmann ML, Schleyerbach R, Kirschbaum BJ: Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases. Immunopharmacology. 2000 May;47(2-3):273-89. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/10878294 # Schattenkirchner M: The use of leflunomide in the treatment of rheumatoid arthritis: an experimental and clinical review. Immunopharmacology. 2000 May;47(2-3):291-8. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/10878295 # Fox RI: Mechanism of action of leflunomide in rheumatoid arthritis. J Rheumatol Suppl. 1998 Jul;53:20-6. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/9666414
n3:group
approved investigational
n3:halfLife
2 weeks
n3:indication
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.
owl:sameAs
n26:DB01097 n30:DB01097
dcterms:title
Leflunomide
adms:identifier
n9:46506013 n10:0555-0351-01 n11:3899 n14:C07905 n15:D00749 n16:DB01097 n17:6402 n18:3762 n28:Leflunomide n29:PA450192
n3:mechanismOfAction
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.
n3:packager
n6:271B3E72-363D-11E5-9242-09173F13E4C5 n6:271B3E73-363D-11E5-9242-09173F13E4C5 n6:271B3E7B-363D-11E5-9242-09173F13E4C5 n6:271B3E7A-363D-11E5-9242-09173F13E4C5 n6:271B3E78-363D-11E5-9242-09173F13E4C5 n6:271B3E79-363D-11E5-9242-09173F13E4C5 n6:271B3E71-363D-11E5-9242-09173F13E4C5 n6:271B3E77-363D-11E5-9242-09173F13E4C5 n6:271B3E74-363D-11E5-9242-09173F13E4C5 n6:271B3E75-363D-11E5-9242-09173F13E4C5 n6:271B3E76-363D-11E5-9242-09173F13E4C5
n3:routeOfElimination
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.
n3:synonym
5-Methyl-N-(4-(trifluoromethyl)phenyl)-4-isoxazolecarboxamide 5-Methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide Leflunomide Leflunomida alpha,alpha,alpha-Trifluoro-5-methyl-4-isoxazolecarboxy-P-toluidide Arava Lefunomide Leflunomidum
n3:toxicity
LD<sub>50</sub>=100-250 mg/kg (acute oral toxicity)
n3:volumeOfDistribution
* 0.13 L/kg
n12:hasAHFSCode
n24:92-00-00
n3:foodInteraction
Take without regard to meals.
n3:proteinBinding
>99.3%
n3:synthesisReference
Ilya Avrutov, "Novel processes for making- and a new crystalline form of- leflunomide." U.S. Patent US20010031878, issued October 18, 2001.
n22:hasConcept
n23:M0132172
foaf:page
n21:leflunomide.htm n27:leflunomide.html
n3:IUPAC-Name
n4:271B3E89-363D-11E5-9242-09173F13E4C5
n3:InChI
n4:271B3E8F-363D-11E5-9242-09173F13E4C5
n3:Molecular-Formula
n4:271B3E8E-363D-11E5-9242-09173F13E4C5
n3:Molecular-Weight
n4:271B3E8B-363D-11E5-9242-09173F13E4C5
n3:Monoisotopic-Weight
n4:271B3E8C-363D-11E5-9242-09173F13E4C5
n3:SMILES
n4:271B3E8D-363D-11E5-9242-09173F13E4C5
n3:Water-Solubility
n4:271B3E87-363D-11E5-9242-09173F13E4C5 n4:271B3E9F-363D-11E5-9242-09173F13E4C5
n3:logP
n4:271B3E85-363D-11E5-9242-09173F13E4C5 n4:271B3E88-363D-11E5-9242-09173F13E4C5 n4:271B3EA1-363D-11E5-9242-09173F13E4C5
n3:logS
n4:271B3E86-363D-11E5-9242-09173F13E4C5
n12:hasATCCode
n13:L04AA13
n3:H-Bond-Acceptor-Count
n4:271B3E95-363D-11E5-9242-09173F13E4C5
n3:H-Bond-Donor-Count
n4:271B3E96-363D-11E5-9242-09173F13E4C5
n3:InChIKey
n4:271B3E90-363D-11E5-9242-09173F13E4C5
n3:Polar-Surface-Area--PSA-
n4:271B3E91-363D-11E5-9242-09173F13E4C5
n3:Polarizability
n4:271B3E93-363D-11E5-9242-09173F13E4C5
n3:Refractivity
n4:271B3E92-363D-11E5-9242-09173F13E4C5
n3:Rotatable-Bond-Count
n4:271B3E94-363D-11E5-9242-09173F13E4C5
n3:absorption
Well absorbed, peak plasma concentrations appear 6-12 hours after dosing
n3:affectedOrganism
Humans and other mammals
n3:casRegistryNumber
75706-12-6
n3:category
n3:containedIn
n7:271B3E7D-363D-11E5-9242-09173F13E4C5 n7:271B3E7E-363D-11E5-9242-09173F13E4C5 n7:271B3E7C-363D-11E5-9242-09173F13E4C5 n7:271B3E7F-363D-11E5-9242-09173F13E4C5
n3:Bioavailability
n4:271B3E9B-363D-11E5-9242-09173F13E4C5
n3:Ghose-Filter
n4:271B3E9D-363D-11E5-9242-09173F13E4C5
n3:MDDR-Like-Rule
n4:271B3E9E-363D-11E5-9242-09173F13E4C5
n3:Melting-Point
n4:271B3EA0-363D-11E5-9242-09173F13E4C5
n3:Number-of-Rings
n4:271B3E9A-363D-11E5-9242-09173F13E4C5
n3:Physiological-Charge
n4:271B3E99-363D-11E5-9242-09173F13E4C5
n3:Rule-of-Five
n4:271B3E9C-363D-11E5-9242-09173F13E4C5
n3:Traditional-IUPAC-Name
n4:271B3E8A-363D-11E5-9242-09173F13E4C5
n3:pKa--strongest-acidic-
n4:271B3E97-363D-11E5-9242-09173F13E4C5
n3:pKa--strongest-basic-
n4:271B3E98-363D-11E5-9242-09173F13E4C5