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Identification
NameLeflunomide
Accession NumberDB01097  (APRD00205)
TypeSmall Molecule
GroupsApproved, Investigational
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.

Structure
Thumb
Synonyms
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
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Aravatablet, film coated10 mg/1oralSanofi Aventis U.S. Llc1998-09-10Not applicableUs
Aravatablet, film coated20 mg/1oralbryant ranch prepack1998-09-10Not applicableUs
Aravatablet, film coated100 mg/1oralSanofi Aventis U.S. Llc1998-09-19Not applicableUs
Aravatablet, film coated20 mg/1oralSanofi Aventis U.S. Llc1998-09-10Not applicableUs
Arava 100 mgtablet100 mgoralSanofi Aventis Canada Inc2000-03-29Not applicableCanada
Arava 10mgtablet10 mgoralSanofi Aventis Canada Inc2000-03-29Not applicableCanada
Arava 20 mgtablet20 mgoralSanofi Aventis Canada Inc2000-03-29Not applicableCanada
Dom-leflunomidetablet20 mgoralDominion PharmacalNot applicableNot applicableCanada
Dom-leflunomidetablet10 mgoralDominion PharmacalNot applicableNot applicableCanada
Leflunomidetablet, film coated20 mg/1oralPrasco LLC1998-09-10Not applicableUs
Leflunomidetablet, film coated10 mg/1oralPrasco LLC1998-09-10Not applicableUs
Leflunomidetablet20 mgoralPro Doc Limitee2013-11-28Not applicableCanada
Leflunomidetablet20 mgoralSanis Health Inc2010-06-15Not applicableCanada
Leflunomidetablet10 mgoralPro Doc Limitee2013-11-28Not applicableCanada
Leflunomidetablet10 mgoralSanis Health Inc2010-06-15Not applicableCanada
Leflunomidetablet, film coated20 mg/1oralWinthrop U.S.2015-09-07Not applicableUs
Leflunomidetablet, film coated10 mg/1oralWinthrop U.S.2015-09-07Not applicableUs
Mylan-leflunomidetablet20 mgoralMylan Pharmaceuticals Ulc2008-11-14Not applicableCanada
Mylan-leflunomidetablet10 mgoralMylan Pharmaceuticals Ulc2008-11-14Not applicableCanada
Ntp-leflunomidetablet20 mgoralTeva Canada LimitedNot applicableNot applicableCanada
Ntp-leflunomidetablet10 mgoralTeva Canada LimitedNot applicableNot applicableCanada
Nu-leflunomidetablet10 mgoralNu Pharm IncNot applicableNot applicableCanada
Nu-leflunomidetablet20 mgoralNu Pharm IncNot applicableNot applicableCanada
PHL-leflunomidetablet10 mgoralPharmel Inc2008-10-31Not applicableCanada
PHL-leflunomidetablet20 mgoralPharmel Inc2008-10-31Not applicableCanada
PMS-leflunomidetablet20 mgoralPharmascience Inc2006-12-01Not applicableCanada
PMS-leflunomidetablet10 mgoralPharmascience Inc2006-12-01Not applicableCanada
Sandoz Leflunomidetablet20 mgoralSandoz Canada Incorporated2006-08-15Not applicableCanada
Sandoz Leflunomidetablet10 mgoralSandoz Canada Incorporated2006-08-15Not applicableCanada
Teva-leflunomidetablet20 mgoralTeva Canada Limited2004-12-21Not applicableCanada
Teva-leflunomidetablet10 mgoralTeva Canada Limited2004-12-21Not applicableCanada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo-leflunomidetablet20 mgoralApotex Inc2004-09-14Not applicableCanada
Apo-leflunomidetablet10 mgoralApotex Inc2004-09-14Not applicableCanada
Leflunomidetablet10 mg/1oralGolden State Medical Supply, Inc.2005-09-13Not applicableUs
Leflunomidetablet10 mg/1oralTrigen Laboratories, LLC2011-05-06Not applicableUs
Leflunomidetablet, film coated10 mg/1oralPhysicians Total Care, Inc.2010-09-17Not applicableUs
Leflunomidetablet, film coated20 mg/1oralTeva Pharmaceuticals USA Inc2005-09-142015-10-31Us
Leflunomidetablet, film coated10 mg/1oralTeva Pharmaceuticals USA Inc2005-09-142015-10-31Us
Leflunomidetablet, film coated20 mg/1oralPhysicians Total Care, Inc.2006-07-10Not applicableUs
Leflunomidetablet20 mg/1oralAvera Mc Kennan Hospital2015-03-01Not applicableUs
Leflunomidetablet20 mg/1oralHeritage Pharmaceuticals Inc2009-10-29Not applicableUs
Leflunomidetablet20 mg/1oralDispensing Solutions, Inc.2009-10-29Not applicableUs
Leflunomidetablet10 mg/1oralHeritage Pharmaceuticals Inc2009-10-29Not applicableUs
Leflunomidetablet20 mg/1oralApotex Corp.2005-09-13Not applicableUs
Leflunomidetablet20 mg/1oralNorth Star Rx Llc2011-05-06Not applicableUs
Leflunomidetablet10 mg/1oralApotex Corp.2005-09-13Not applicableUs
Leflunomidetablet10 mg/1oralNorth Star Rx Llc2011-05-06Not applicableUs
Leflunomidetablet20 mg/1oralGolden State Medical Supply, Inc.2005-09-13Not applicableUs
Leflunomidetablet20 mg/1oralTrigen Laboratories, LLC2011-05-06Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIG162GK9U4W
CAS number75706-12-6
WeightAverage: 270.2073
Monoisotopic: 270.061612157
Chemical FormulaC12H9F3N2O2
InChI KeyInChIKey=VHOGYURTWQBHIL-UHFFFAOYSA-N
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)
IUPAC Name
5-methyl-N-[4-(trifluoromethyl)phenyl]-1,2-oxazole-4-carboxamide
SMILES
CC1=C(C=NO1)C(=O)NC1=CC=C(C=C1)C(F)(F)F
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as n-arylamides. These are organic compounds that contain a carboxamide group that is N-linked to a aryl group. They have the generic structure RC(=O)N(R')H, R = organyl group and R'= aryl group.
KingdomOrganic compounds
Super ClassOrganonitrogen compounds
ClassN-arylamides
Sub ClassNot Available
Direct ParentN-arylamides
Alternative Parents
Substituents
  • N-arylamide
  • Benzenoid
  • Monocyclic benzene moiety
  • Heteroaromatic compound
  • Oxazole
  • Isoxazole
  • Azole
  • Secondary carboxylic acid amide
  • Carboxamide group
  • Oxacycle
  • Azacycle
  • Organoheterocyclic compound
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organofluoride
  • Organohalogen compound
  • Carbonyl group
  • Alkyl halide
  • Alkyl fluoride
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Pharmacology
IndicationFor 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.
PharmacodynamicsLeflunomide 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.
Mechanism of actionLeflunomide 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.
Related Articles
AbsorptionWell 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.

SubstrateEnzymesProduct
Leflunomide
A771726Details
Route of eliminationThe 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 life2 weeks
ClearanceNot Available
ToxicityLD50=100-250 mg/kg (acute oral toxicity)
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug Reactions
Interacting Gene/EnzymeSNP RS IDAllele nameDefining changeAdverse ReactionReference(s)
Cytochrome P450 1A2
Gene symbol: CYP1A2
UniProt: P05177
rs762551 Not AvailableC alleleDiarrhea, vomiting, liver toxicity, headache, insomnia, rash, alopecia, hypertension, leucopenia, asthma18496682
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9949
Caco-2 permeable+0.5069
P-glycoprotein substrateNon-substrate0.909
P-glycoprotein inhibitor INon-inhibitor0.7822
P-glycoprotein inhibitor IINon-inhibitor0.8889
Renal organic cation transporterNon-inhibitor0.9154
CYP450 2C9 substrateNon-substrate0.8548
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.5211
CYP450 1A2 substrateInhibitor0.9189
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-inhibitor0.5117
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5622
Ames testNon AMES toxic0.5504
CarcinogenicityNon-carcinogens0.7067
BiodegradationNot ready biodegradable0.9836
Rat acute toxicity3.0297 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9879
hERG inhibition (predictor II)Non-inhibitor0.9068
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Tablet, film coatedoral10 mg/1
Tablet, film coatedoral100 mg/1
Tablet, film coatedoral20 mg/1
Tabletoral100 mg
Tabletoral10 mg
Tabletoral20 mg
Tabletoral10 mg/1
Tabletoral20 mg/1
Prices
Unit descriptionCostUnit
Arava 10 mg tablet24.76USD tablet
Arava 20 mg tablet24.76USD tablet
Leflunomide 10 mg tablet16.75USD tablet
Leflunomide 20 mg tablet16.75USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point165-166 °CNot Available
water solubility21 mg/L (poorly soluble)Not Available
logP2.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0844 mg/mLALOGPS
logP2.52ALOGPS
logP2.51ChemAxon
logS-3.5ALOGPS
pKa (Strongest Acidic)10.41ChemAxon
pKa (Strongest Basic)-0.45ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area55.13 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity64.16 m3·mol-1ChemAxon
Polarizability23.11 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Ilya Avrutov, “Novel processes for making- and a new crystalline form of- leflunomide.” U.S. Patent US20010031878, issued October 18, 2001.

US20010031878
General References
  1. Goldenberg MM: Leflunomide, a novel immunomodulator for the treatment of active rheumatoid arthritis. Clin Ther. 1999 Nov;21(11):1837-52; discussion 1821. [PubMed:10890256 ]
  2. Li EK, Tam LS, Tomlinson B: Leflunomide in the treatment of rheumatoid arthritis. Clin Ther. 2004 Apr;26(4):447-59. [PubMed:15189743 ]
  3. Sanders S, Harisdangkul V: Leflunomide for the treatment of rheumatoid arthritis and autoimmunity. Am J Med Sci. 2002 Apr;323(4):190-3. [PubMed:12003373 ]
  4. Breedveld FC, Dayer JM: Leflunomide: mode of action in the treatment of rheumatoid arthritis. Ann Rheum Dis. 2000 Nov;59(11):841-9. [PubMed:11053058 ]
  5. Reitzik M, Lownie JF: Familial polyostotic fibrous dysplasia. Oral Surg Oral Med Oral Pathol. 1975 Dec;40(6):769-74. [PubMed:1060033 ]
  6. 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:10878294 ]
  7. 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:10878295 ]
  8. Fox RI: Mechanism of action of leflunomide in rheumatoid arthritis. J Rheumatol Suppl. 1998 Jul;53:20-6. [PubMed:9666414 ]
External Links
ATC CodesL04AA13
AHFS Codes
  • 92:00.00
PDB Entries
FDA labelDownload (1.23 MB)
MSDSDownload (105 KB)
Interactions
Drug Interactions
Drug
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Leflunomide.
AcenocoumarolLeflunomide may increase the anticoagulant activities of Acenocoumarol.
Activated charcoalThe serum concentration of the active metabolites of Leflunomide can be reduced when Leflunomide is used in combination with Activated charcoal resulting in a loss in efficacy.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Leflunomide.
Ado-trastuzumab emtansineThe risk or severity of adverse effects can be increased when ado-trastuzumab emtansine is combined with Leflunomide.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Leflunomide.
AltretamineThe risk or severity of adverse effects can be increased when Altretamine is combined with Leflunomide.
AmsacrineThe risk or severity of adverse effects can be increased when Amsacrine is combined with Leflunomide.
AnakinraThe risk or severity of adverse effects can be increased when Anakinra is combined with Leflunomide.
Anti-thymocyte Globulin (Rabbit)The risk or severity of adverse effects can be increased when Anti-thymocyte Globulin (Rabbit) is combined with Leflunomide.
AzacitidineThe risk or severity of adverse effects can be increased when Azacitidine is combined with Leflunomide.
AzathioprineThe risk or severity of adverse effects can be increased when Azathioprine is combined with Leflunomide.
BasilThe risk or severity of adverse effects can be increased when Basil is combined with Leflunomide.
BasiliximabThe risk or severity of adverse effects can be increased when Basiliximab is combined with Leflunomide.
BelataceptThe risk or severity of adverse effects can be increased when Belatacept is combined with Leflunomide.
BelimumabThe risk or severity of adverse effects can be increased when Belimumab is combined with Leflunomide.
BetamethasoneThe risk or severity of adverse effects can be increased when Betamethasone is combined with Leflunomide.
BleomycinThe risk or severity of adverse effects can be increased when Bleomycin is combined with Leflunomide.
BlinatumomabThe risk or severity of adverse effects can be increased when Blinatumomab is combined with Leflunomide.
BosentanThe serum concentration of Bosentan can be increased when it is combined with Leflunomide.
Brentuximab vedotinThe risk or severity of adverse effects can be increased when Brentuximab vedotin is combined with Leflunomide.
BudesonideThe risk or severity of adverse effects can be increased when Budesonide is combined with Leflunomide.
BusulfanThe risk or severity of adverse effects can be increased when Busulfan is combined with Leflunomide.
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Leflunomide.
CanakinumabThe risk or severity of adverse effects can be increased when Canakinumab is combined with Leflunomide.
CapecitabineThe risk or severity of adverse effects can be increased when Capecitabine is combined with Leflunomide.
CarboplatinThe risk or severity of adverse effects can be increased when Carboplatin is combined with Leflunomide.
CarmustineThe risk or severity of adverse effects can be increased when Carmustine is combined with Leflunomide.
CarvedilolThe serum concentration of Carvedilol can be increased when it is combined with Leflunomide.
Certolizumab pegolThe risk or severity of adverse effects can be increased when Certolizumab pegol is combined with Leflunomide.
ChlorambucilThe risk or severity of adverse effects can be increased when Chlorambucil is combined with Leflunomide.
CholestyramineThe serum concentration of the active metabolites of Leflunomide can be reduced when Leflunomide is used in combination with Cholestyramine resulting in a loss in efficacy.
CisplatinThe risk or severity of adverse effects can be increased when Cisplatin is combined with Leflunomide.
CladribineThe risk or severity of adverse effects can be increased when Cladribine is combined with Leflunomide.
ClofarabineThe risk or severity of adverse effects can be increased when Clofarabine is combined with Leflunomide.
ColesevelamThe serum concentration of the active metabolites of Leflunomide can be reduced when Leflunomide is used in combination with Colesevelam resulting in a loss in efficacy.
ColestipolThe serum concentration of the active metabolites of Leflunomide can be reduced when Leflunomide is used in combination with Colestipol resulting in a loss in efficacy.
CorticotropinThe risk or severity of adverse effects can be increased when Corticotropin is combined with Leflunomide.
Cortisone acetateThe risk or severity of adverse effects can be increased when Cortisone acetate is combined with Leflunomide.
CyclophosphamideThe risk or severity of adverse effects can be increased when Cyclophosphamide is combined with Leflunomide.
CyclosporineThe risk or severity of adverse effects can be increased when Cyclosporine is combined with Leflunomide.
CytarabineThe risk or severity of adverse effects can be increased when Cytarabine is combined with Leflunomide.
DacarbazineThe risk or severity of adverse effects can be increased when Dacarbazine is combined with Leflunomide.
DactinomycinThe risk or severity of adverse effects can be increased when Dactinomycin is combined with Leflunomide.
DasatinibThe risk or severity of adverse effects can be increased when Dasatinib is combined with Leflunomide.
DaunorubicinThe risk or severity of adverse effects can be increased when Daunorubicin is combined with Leflunomide.
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Leflunomide.
DexamethasoneThe risk or severity of adverse effects can be increased when Dexamethasone is combined with Leflunomide.
DicoumarolLeflunomide may increase the anticoagulant activities of Dicoumarol.
DinutuximabThe risk or severity of adverse effects can be increased when Dinutuximab is combined with Leflunomide.
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Leflunomide.
DoxorubicinThe risk or severity of adverse effects can be increased when Doxorubicin is combined with Leflunomide.
DronabinolThe serum concentration of Dronabinol can be increased when it is combined with Leflunomide.
EculizumabThe risk or severity of adverse effects can be increased when Eculizumab is combined with Leflunomide.
EpirubicinThe risk or severity of adverse effects can be increased when Epirubicin is combined with Leflunomide.
EstramustineThe risk or severity of adverse effects can be increased when Estramustine is combined with Leflunomide.
EtanerceptThe risk or severity of adverse effects can be increased when Etanercept is combined with Leflunomide.
EtoposideThe risk or severity of adverse effects can be increased when Etoposide is combined with Leflunomide.
EverolimusThe risk or severity of adverse effects can be increased when Everolimus is combined with Leflunomide.
FingolimodThe risk or severity of adverse effects can be increased when Fingolimod is combined with Leflunomide.
FloxuridineThe risk or severity of adverse effects can be increased when Floxuridine is combined with Leflunomide.
FludarabineThe risk or severity of adverse effects can be increased when Fludarabine is combined with Leflunomide.
FludrocortisoneThe risk or severity of adverse effects can be increased when Fludrocortisone is combined with Leflunomide.
FluorouracilThe risk or severity of adverse effects can be increased when Fluorouracil is combined with Leflunomide.
GemcitabineThe risk or severity of adverse effects can be increased when Gemcitabine is combined with Leflunomide.
Gemtuzumab ozogamicinThe risk or severity of adverse effects can be increased when Gemtuzumab ozogamicin is combined with Leflunomide.
Glatiramer AcetateThe risk or severity of adverse effects can be increased when Glatiramer Acetate is combined with Leflunomide.
golimumabThe risk or severity of adverse effects can be increased when golimumab is combined with Leflunomide.
HydrocortisoneThe risk or severity of adverse effects can be increased when Hydrocortisone is combined with Leflunomide.
HydroxyureaThe risk or severity of adverse effects can be increased when Hydroxyurea is combined with Leflunomide.
Ibritumomab tiuxetanThe risk or severity of adverse effects can be increased when Ibritumomab is combined with Leflunomide.
IbrutinibThe risk or severity of adverse effects can be increased when Ibrutinib is combined with Leflunomide.
IdarubicinThe risk or severity of adverse effects can be increased when Idarubicin is combined with Leflunomide.
IdelalisibThe risk or severity of adverse effects can be increased when Idelalisib is combined with Leflunomide.
IfosfamideThe risk or severity of adverse effects can be increased when Ifosfamide is combined with Leflunomide.
ImatinibThe risk or severity of adverse effects can be increased when Imatinib is combined with Leflunomide.
ImiquimodThe risk or severity of adverse effects can be increased when Imiquimod is combined with Leflunomide.
InfliximabThe risk or severity of adverse effects can be increased when Infliximab is combined with Leflunomide.
IrinotecanThe risk or severity of adverse effects can be increased when Irinotecan is combined with Leflunomide.
L-PhenylalanineThe risk or severity of adverse effects can be increased when L-Phenylalanine is combined with Leflunomide.
LenalidomideThe risk or severity of adverse effects can be increased when Lenalidomide is combined with Leflunomide.
LomustineThe risk or severity of adverse effects can be increased when Lomustine is combined with Leflunomide.
MechlorethamineThe risk or severity of adverse effects can be increased when Mechlorethamine is combined with Leflunomide.
MelphalanThe risk or severity of adverse effects can be increased when Melphalan is combined with Leflunomide.
MercaptopurineThe risk or severity of adverse effects can be increased when Mercaptopurine is combined with Leflunomide.
MethotrexateThe risk or severity of adverse effects can be increased when Methotrexate is combined with Leflunomide.
MethylprednisoloneThe risk or severity of adverse effects can be increased when Methylprednisolone is combined with Leflunomide.
MitomycinThe risk or severity of adverse effects can be increased when Mitomycin is combined with Leflunomide.
MitoxantroneThe risk or severity of adverse effects can be increased when Mitoxantrone is combined with Leflunomide.
Mycophenolate mofetilThe risk or severity of adverse effects can be increased when Mycophenolate mofetil is combined with Leflunomide.
Mycophenolic acidThe risk or severity of adverse effects can be increased when Mycophenolic acid is combined with Leflunomide.
NatalizumabThe risk or severity of adverse effects can be increased when Leflunomide is combined with Natalizumab.
NelarabineThe risk or severity of adverse effects can be increased when Nelarabine is combined with Leflunomide.
NilotinibThe risk or severity of adverse effects can be increased when Nilotinib is combined with Leflunomide.
ObinutuzumabThe risk or severity of adverse effects can be increased when Obinutuzumab is combined with Leflunomide.
OsimertinibThe risk or severity of adverse effects can be increased when Osimertinib is combined with Leflunomide.
OxaliplatinThe risk or severity of adverse effects can be increased when Oxaliplatin is combined with Leflunomide.
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Leflunomide.
PalbociclibThe risk or severity of adverse effects can be increased when Palbociclib is combined with Leflunomide.
PanobinostatThe risk or severity of adverse effects can be increased when Panobinostat is combined with Leflunomide.
PazopanibThe risk or severity of adverse effects can be increased when Pazopanib is combined with Leflunomide.
PegaspargaseThe risk or severity of adverse effects can be increased when Pegaspargase is combined with Leflunomide.
PemetrexedThe risk or severity of adverse effects can be increased when Pemetrexed is combined with Leflunomide.
PentostatinThe risk or severity of adverse effects can be increased when Pentostatin is combined with Leflunomide.
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Leflunomide.
PomalidomideThe risk or severity of adverse effects can be increased when Pomalidomide is combined with Leflunomide.
PralatrexateThe risk or severity of adverse effects can be increased when Pralatrexate is combined with Leflunomide.
PrednisoloneThe risk or severity of adverse effects can be increased when Prednisolone is combined with Leflunomide.
PrednisoneThe risk or severity of adverse effects can be increased when Prednisone is combined with Leflunomide.
ProcarbazineThe risk or severity of adverse effects can be increased when Procarbazine is combined with Leflunomide.
Repository corticotropinThe risk or severity of adverse effects can be increased when Repository corticotropin is combined with Leflunomide.
RifampicinThe serum concentration of the active metabolites of Leflunomide can be increased when Leflunomide is used in combination with Rifampicin.
RilonaceptThe risk or severity of adverse effects can be increased when Rilonacept is combined with Leflunomide.
RituximabThe risk or severity of adverse effects can be increased when Rituximab is combined with Leflunomide.
RoflumilastRoflumilast may increase the immunosuppressive activities of Leflunomide.
RuxolitinibThe risk or severity of adverse effects can be increased when Ruxolitinib is combined with Leflunomide.
SecukinumabThe risk or severity of adverse effects can be increased when Secukinumab is combined with Leflunomide.
SildenafilThe metabolism of Sildenafil can be decreased when combined with Leflunomide.
SiltuximabThe risk or severity of adverse effects can be increased when Siltuximab is combined with Leflunomide.
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Leflunomide.
SirolimusThe risk or severity of adverse effects can be increased when Sirolimus is combined with Leflunomide.
SorafenibThe risk or severity of adverse effects can be increased when Sorafenib is combined with Leflunomide.
StreptozocinThe risk or severity of adverse effects can be increased when Streptozocin is combined with Leflunomide.
SunitinibThe risk or severity of adverse effects can be increased when Sunitinib is combined with Leflunomide.
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Leflunomide.
TemozolomideThe risk or severity of adverse effects can be increased when Temozolomide is combined with Leflunomide.
TemsirolimusThe risk or severity of adverse effects can be increased when Temsirolimus is combined with Leflunomide.
TeniposideThe risk or severity of adverse effects can be increased when Teniposide is combined with Leflunomide.
TeriflunomideThe risk or severity of adverse effects can be increased when Leflunomide is combined with Teriflunomide.
ThalidomideThe risk or severity of adverse effects can be increased when Thalidomide is combined with Leflunomide.
ThiotepaThe risk or severity of adverse effects can be increased when Thiotepa is combined with Leflunomide.
TioguanineThe risk or severity of adverse effects can be increased when Tioguanine is combined with Leflunomide.
TocilizumabThe risk or severity of adverse effects can be increased when Tocilizumab is combined with Leflunomide.
TofacitinibLeflunomide may increase the immunosuppressive activities of Tofacitinib.
TolbutamideThe serum concentration of Tolbutamide can be increased when it is combined with Leflunomide.
TopotecanThe risk or severity of adverse effects can be increased when Topotecan is combined with Leflunomide.
TositumomabThe risk or severity of adverse effects can be increased when Tositumomab is combined with Leflunomide.
TrabectedinThe risk or severity of adverse effects can be increased when Trabectedin is combined with Leflunomide.
TrastuzumabTrastuzumab may increase the neutropenic activities of Leflunomide.
TretinoinThe risk or severity of adverse effects can be increased when Tretinoin is combined with Leflunomide.
TriamcinoloneThe risk or severity of adverse effects can be increased when Triamcinolone is combined with Leflunomide.
UstekinumabThe risk or severity of adverse effects can be increased when Ustekinumab is combined with Leflunomide.
VedolizumabThe risk or severity of adverse effects can be increased when Vedolizumab is combined with Leflunomide.
VinblastineThe risk or severity of adverse effects can be increased when Vinblastine is combined with Leflunomide.
VincristineThe risk or severity of adverse effects can be increased when Vincristine is combined with Leflunomide.
VindesineThe risk or severity of adverse effects can be increased when Vindesine is combined with Leflunomide.
VinorelbineThe risk or severity of adverse effects can be increased when Vinorelbine is combined with Leflunomide.
WarfarinLeflunomide may increase the anticoagulant activities of Warfarin.
Food Interactions
  • Take without regard to meals.

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Ubiquinone binding
Specific Function:
Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
Gene Name:
DHODH
Uniprot ID:
Q02127
Molecular Weight:
42866.93 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
  2. Goldenberg MM: Leflunomide, a novel immunomodulator for the treatment of active rheumatoid arthritis. Clin Ther. 1999 Nov;21(11):1837-52; discussion 1821. [PubMed:10890256 ]
  3. Prakash A, Jarvis B: Leflunomide: a review of its use in active rheumatoid arthritis. Drugs. 1999 Dec;58(6):1137-64. [PubMed:10651393 ]
  4. Li EK, Tam LS, Tomlinson B: Leflunomide in the treatment of rheumatoid arthritis. Clin Ther. 2004 Apr;26(4):447-59. [PubMed:15189743 ]
  5. Wozel G, Pfeiffer C: [Leflunomide--a new drug for pharmacological immunomodulation]. Hautarzt. 2002 May;53(5):309-15. [PubMed:12063741 ]
  6. Sanders S, Harisdangkul V: Leflunomide for the treatment of rheumatoid arthritis and autoimmunity. Am J Med Sci. 2002 Apr;323(4):190-3. [PubMed:12003373 ]
  7. Breedveld FC, Dayer JM: Leflunomide: mode of action in the treatment of rheumatoid arthritis. Ann Rheum Dis. 2000 Nov;59(11):841-9. [PubMed:11053058 ]
  8. Reitzik M, Lownie JF: Familial polyostotic fibrous dysplasia. Oral Surg Oral Med Oral Pathol. 1975 Dec;40(6):769-74. [PubMed:1060033 ]
  9. 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:10878294 ]
  10. 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:10878295 ]
  11. Fox RI: Mechanism of action of leflunomide in rheumatoid arthritis. J Rheumatol Suppl. 1998 Jul;53:20-6. [PubMed:9666414 ]
  12. Fukushima R, Kanamori S, Hirashiba M, Hishikawa A, Muranaka RI, Kaneto M, Nakamura K, Kato I: Teratogenicity study of the dihydroorotate-dehydrogenase inhibitor and protein tyrosine kinase inhibitor Leflunomide in mice. Reprod Toxicol. 2007 Nov-Dec;24(3-4):310-6. Epub 2007 May 18. [PubMed:17604599 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
agonist
General Function:
Transcription regulatory region dna binding
Specific Function:
Ligand-activated transcriptional activator. Binds to the XRE promoter region of genes it activates. Activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes (such as the CYP1A1 gene). Mediates biochemical and toxic effects of halogenated aromatic hydrocarbons. Involved in cell-cycle regulation. Likely to play an important role in the development and matu...
Gene Name:
AHR
Uniprot ID:
P35869
Molecular Weight:
96146.705 Da
References
  1. O'Donnell EF, Saili KS, Koch DC, Kopparapu PR, Farrer D, Bisson WH, Mathew LK, Sengupta S, Kerkvliet NI, Tanguay RL, Kolluri SK: The anti-inflammatory drug leflunomide is an agonist of the aryl hydrocarbon receptor. PLoS One. 2010 Oct 1;5(10). pii: e13128. doi: 10.1371/journal.pone.0013128. [PubMed:20957046 ]
  2. Hu W, Sorrentino C, Denison MS, Kolaja K, Fielden MR: Induction of cyp1a1 is a nonspecific biomarker of aryl hydrocarbon receptor activation: results of large scale screening of pharmaceuticals and toxicants in vivo and in vitro. Mol Pharmacol. 2007 Jun;71(6):1475-86. Epub 2007 Feb 27. [PubMed:17327465 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
antagonist
General Function:
Signal transducer activity
Specific Function:
Non-receptor protein-tyrosine kinase that regulates reorganization of the actin cytoskeleton, cell polarization, cell migration, adhesion, spreading and bone remodeling. Plays a role in the regulation of the humoral immune response, and is required for normal levels of marginal B-cells in the spleen and normal migration of splenic B-cells. Required for normal macrophage polarization and migrati...
Gene Name:
PTK2B
Uniprot ID:
Q14289
Molecular Weight:
115873.62 Da
References
  1. Pytel D, Sliwinski T, Poplawski T, Ferriola D, Majsterek I: Tyrosine kinase blockers: new hope for successful cancer therapy. Anticancer Agents Med Chem. 2009 Jan;9(1):66-76. [PubMed:19149483 ]
  2. Fukushima R, Kanamori S, Hirashiba M, Hishikawa A, Muranaka RI, Kaneto M, Nakamura K, Kato I: Teratogenicity study of the dihydroorotate-dehydrogenase inhibitor and protein tyrosine kinase inhibitor Leflunomide in mice. Reprod Toxicol. 2007 Nov-Dec;24(3-4):310-6. Epub 2007 May 18. [PubMed:17604599 ]
  3. Steeghs N, Nortier JW, Gelderblom H: Small molecule tyrosine kinase inhibitors in the treatment of solid tumors: an update of recent developments. Ann Surg Oncol. 2007 Feb;14(2):942-53. Epub 2006 Nov 14. [PubMed:17103252 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
General Function:
Steroid hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenyto...
Gene Name:
CYP2C9
Uniprot ID:
P11712
Molecular Weight:
55627.365 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
  2. Sevilla-Mantilla C, Ortega L, Agundez JA, Fernandez-Gutierrez B, Ladero JM, Diaz-Rubio M: Leflunomide-induced acute hepatitis. Dig Liver Dis. 2004 Jan;36(1):82-4. [PubMed:14971821 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N...
Gene Name:
CYP1A2
Uniprot ID:
P05177
Molecular Weight:
58293.76 Da
References
  1. Wang B, Zhou SF: Synthetic and natural compounds that interact with human cytochrome P450 1A2 and implications in drug development. Curr Med Chem. 2009;16(31):4066-218. [PubMed:19754423 ]
  2. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014 ]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from t...
Gene Name:
ABCG2
Uniprot ID:
Q9UNQ0
Molecular Weight:
72313.47 Da
References
  1. Kis E, Nagy T, Jani M, Molnar E, Janossy J, Ujhellyi O, Nemet K, Heredi-Szabo K, Krajcsi P: Leflunomide and its metabolite A771726 are high affinity substrates of BCRP: implications for drug resistance. Ann Rheum Dis. 2009 Jul;68(7):1201-7. doi: 10.1136/ard.2007.086264. Epub 2008 Apr 8. [PubMed:18397960 ]
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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13