Identification

Name
Leflunomide
Accession Number
DB01097  (APRD00205)
Type
Small Molecule
Groups
Approved, 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
  • Leflunomida
  • Leflunomide
  • Léflunomide
  • Leflunomidum
External IDs
SU-101 / SU101
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AravaTablet, film coated20 mg/1Oralbryant ranch prepack1998-09-10Not applicableUs
AravaTablet, film coated20 mgOralSanofi Aventis Deutschland Gmb H1999-09-02Not applicableEu
AravaTablet, film coated10 mgOralSanofi Aventis Deutschland Gmb H1999-09-02Not applicableEu
AravaTablet, film coated20 mgOralSanofi Aventis Deutschland Gmb H1999-09-02Not applicableEu
AravaTablet, film coated20 mg/1Oralsanofi-aventis U.S. LLC1998-09-10Not applicableUs
AravaTablet, film coated20 mgOralSanofi Aventis Deutschland Gmb H1999-09-02Not applicableEu
AravaTablet, film coated10 mgOralSanofi Aventis Deutschland Gmb H1999-09-02Not applicableEu
AravaTablet, film coated20 mgOralSanofi Aventis Deutschland Gmb H1999-09-02Not applicableEu
AravaTablet, film coated10 mg/1Oralsanofi-aventis U.S. LLC1998-09-10Not applicableUs
AravaTablet, film coated10 mgOralSanofi Aventis Deutschland Gmb H1999-09-02Not applicableEu
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo-leflunomideTablet10 mgOralApotex Corporation2004-09-14Not applicableCanada
Apo-leflunomideTablet20 mgOralApotex Corporation2004-09-14Not applicableCanada
Dom-leflunomideTablet10 mgOralDominion PharmacalNot applicableNot applicableCanada
Dom-leflunomideTablet20 mgOralDominion PharmacalNot applicableNot applicableCanada
LeflunomideTablet, film coated20 mg/1OralPhysicians Total Care, Inc.2006-07-10Not applicableUs
LeflunomideTablet20 mg/1OralAlembic Pharmaceuticals Limited2016-12-01Not applicableUs
LeflunomideTablet20 mg/1OralAlembic Pharmaceuticals Inc.2016-12-01Not applicableUs
LeflunomideTablet20 mg/1OralPar Pharmaceutical2007-09-242009-09-22Us
LeflunomideTablet, film coated20 mg/1OralTeva2005-09-142015-10-31Us00093 0174 56 nlmimage10 96294b5a
LeflunomideTablet20 mg/1OralApotex Corp.2005-09-13Not applicableUs
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Leflunomide TevaLeflunomide (20 mg)Tablet, film coatedOralTeva Pharma B.V.2011-03-102014-03-18Eu
Leflunomide TevaLeflunomide (10 mg)Tablet, film coatedOralTeva Pharma B.V.2011-03-102014-03-18Eu
Leflunomide TevaLeflunomide (10 mg)Tablet, film coatedOralTeva Pharma B.V.2011-03-102014-03-18Eu
Leflunomide TevaLeflunomide (20 mg)Tablet, film coatedOralTeva Pharma B.V.2011-03-102014-03-18Eu
Leflunomide TevaLeflunomide (10 mg)Tablet, film coatedOralTeva Pharma B.V.2011-03-102014-03-18Eu
Leflunomide TevaLeflunomide (10 mg)Tablet, film coatedOralTeva Pharma B.V.2011-03-102014-03-18Eu
Leflunomide TevaLeflunomide (20 mg)Tablet, film coatedOralTeva Pharma B.V.2011-03-102014-03-18Eu
Leflunomide TevaLeflunomide (20 mg)Tablet, film coatedOralTeva Pharma B.V.2011-03-102014-03-18Eu
Leflunomide TevaLeflunomide (10 mg)Tablet, film coatedOralTeva Pharma B.V.2011-03-102014-03-18Eu
Leflunomide TevaLeflunomide (20 mg)Tablet, film coatedOralTeva Pharma B.V.2011-03-102014-03-18Eu
International/Other Brands
Arava
Categories
UNII
G162GK9U4W
CAS number
75706-12-6
Weight
Average: 270.2073
Monoisotopic: 270.061612157
Chemical Formula
C12H9F3N2O2
InChI Key
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

Pharmacology

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.

Associated Conditions
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.

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.

TargetActionsOrganism
ADihydroorotate dehydrogenase (quinone), mitochondrial
inhibitor
Human
UAryl hydrocarbon receptor
agonist
Human
UProtein-tyrosine kinase 2-beta
antagonist
Human
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

Clearance
Not Available
Toxicity

LD50=100-250 mg/kg (acute oral toxicity)

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Cytochrome P450 1A2---(C;C)C alleleADR Directly StudiedThe presence of this genotype in CYP1A2 may be associated with an increased risk of drug-related toxicity from leflunomide therapy.Details

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe therapeutic efficacy of (R)-warfarin can be increased when used in combination with Leflunomide.
(S)-WarfarinThe therapeutic efficacy of (S)-Warfarin can be increased when used in combination with Leflunomide.
2-MethoxyethanolThe risk or severity of adverse effects can be increased when Leflunomide is combined with 2-Methoxyethanol.
3-isobutyl-1-methyl-7H-xanthineThe serum concentration of 3-isobutyl-1-methyl-7H-xanthine can be increased when it is combined with Leflunomide.
4-hydroxycoumarinThe therapeutic efficacy of 4-hydroxycoumarin can be increased when used in combination with Leflunomide.
6-O-benzylguanineThe serum concentration of 6-O-benzylguanine can be increased when it is combined with Leflunomide.
7-DeazaguanineThe serum concentration of 7-Deazaguanine can be increased when it is combined with Leflunomide.
7,9-DimethylguanineThe serum concentration of 7,9-Dimethylguanine can be increased when it is combined with Leflunomide.
8-azaguanineThe serum concentration of 8-azaguanine can be increased when it is combined with Leflunomide.
8-chlorotheophyllineThe serum concentration of 8-chlorotheophylline can be increased when it is combined with Leflunomide.
Food Interactions
  • Take without regard to meals.

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
Human Metabolome Database
HMDB0015229
KEGG Drug
D00749
KEGG Compound
C07905
PubChem Compound
3899
PubChem Substance
46506013
ChemSpider
3762
BindingDB
50054601
ChEBI
6402
ChEMBL
CHEMBL960
Therapeutic Targets Database
DAP000636
PharmGKB
PA450192
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Leflunomide
ATC Codes
L04AA13 — Leflunomide
AHFS Codes
  • 92:36.00 — Disease-modifying Antirheumatic Agents
FDA label
Download (1.23 MB)
MSDS
Download (105 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers2
1CompletedNot AvailableTo Determine the Bioequivalence Study Under Fasting1
1CompletedOtherTo Determine Bioequivalence Under Fed Conditions1
1CompletedTreatmentGliomas / Sarcomas1
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
1CompletedTreatmentPsoriatic Arthritis / Rheumatoid Arthritis1
1TerminatedTreatmentMelanoma1
1, 2Active Not RecruitingTreatmentRecurrent Plasma Cell Myeloma / Refractory Plasma Cell Myeloma1
1, 2Not Yet RecruitingTreatmentBreast Diseases / Metastatic Triple Negative Breast Cancer / Neoplasms, Breast1
2CompletedTreatmentAdult-Onset Still's Disease1
2CompletedTreatmentBrain and Central Nervous System Tumors1
2CompletedTreatmentRheumatoid Arthritis1
2CompletedTreatmentSystemic Lupus Eythematosus (SLE)1
2CompletedTreatmentUveitis1
2RecruitingTreatmentHenoch-Schoenlein Purpura Nephritis1
2TerminatedPreventionViral sepsis / Viruria1
2Unknown StatusTreatmentBullous Pemphigoid (BP)1
2WithdrawnTreatmentSystemic Lupus Erythematosus (SLE)1
2, 3CompletedTreatmentProstate Cancer1
3CompletedTreatmentBrain and Central Nervous System Tumors1
3CompletedTreatmentRheumatoid Arthritis7
3Not Yet RecruitingTreatmentPolymyalgia Rheumatica1
3RecruitingTreatmentMyasthenia Gravis1
3TerminatedTreatmentNephritis, Lupus1
4CompletedTreatmentRheumatoid Arthritis6
4Enrolling by InvitationBasic ScienceRheumatoid Arthritis1
4Not Yet RecruitingTreatmentPsoriatic Arthritis1
4RecruitingTreatmentImmunoglobulin G4 Related Sclerosing Disease1
4RecruitingTreatmentRheumatoid Arthritis2
4TerminatedTreatmentRheumatoid Arthritis1
4Unknown StatusTreatmentJuvenile Idiopathic Arthritis (JIA)1
4Unknown StatusTreatmentRheumatoid Arthritis1
Not AvailableCompletedBasic ScienceRheumatoid Arthritis1
Not AvailableCompletedTreatmentRheumatoid Arthritis1
Not AvailableRecruitingTreatmentAutoimmune Diseases1
Not AvailableRecruitingTreatmentLupus / Nephritis1
Not AvailableUnknown StatusTreatmentBK Virus Infection / Terminal Renal Failure1
Not AvailableUnknown StatusTreatmentRheumatoid Arthritis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Apotex Inc.
  • Barr Pharmaceuticals
  • Diversified Healthcare Services Inc.
  • Heritage Pharmaceuticals
  • Kali Laboratories Inc.
  • Murfreesboro Pharmaceutical Nursing Supply
  • Physicians Total Care Inc.
  • Prasco Labs
  • Sandoz
  • Sanofi-Aventis Inc.
  • Teva Pharmaceutical Industries Ltd.
Dosage forms
FormRouteStrength
Tablet, film coatedOral10 mg
Tablet, film coatedOral100 mg/1
Tablet, film coatedOral100 mg
Tablet, film coatedOral20 mg
TabletOral100 mg
TabletOral10 mg
TabletOral20 mg
TabletOral10 mg/1
TabletOral20 mg/1
Tablet, film coatedOral10 mg/1
Tablet, film coatedOral20 mg/1
Tablet, film coatedOral15 mg
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.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)165-166 °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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-00di-0390000000-1ac4065d1ef245442a16
MS/MS Spectrum - , positiveLC-MS/MSsplash10-03di-2920000000-819d0674f452a60be1a4

Taxonomy

Description
This compound belongs to the class of organic compounds known as aromatic anilides. These are aromatic compounds containing an anilide group in which the carboxamide group is substituted with an aromatic group. They have the general structure RNC(=O)R', where R= benzene, and R = aryl group.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Anilides
Direct Parent
Aromatic anilides
Alternative Parents
Trifluoromethylbenzenes / Isoxazoles / Heteroaromatic compounds / Secondary carboxylic acid amides / Oxacyclic compounds / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds / Organonitrogen compounds / Organofluorides
show 3 more
Substituents
Aromatic anilide / Trifluoromethylbenzene / Azole / Isoxazole / Heteroaromatic compound / Carboxamide group / Secondary carboxylic acid amide / Carboxylic acid derivative / Organoheterocyclic compound / Azacycle
show 13 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
monocarboxylic acid amide, isoxazoles, (trifluoromethyl)benzenes (CHEBI:6402)

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
Uniprot Name
Dihydroorotate dehydrogenase (quinone), mitochondrial
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...
Gene Name
AHR
Uniprot ID
P35869
Uniprot Name
Aryl hydrocarbon receptor
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 regulat...
Gene Name
PTK2B
Uniprot ID
Q14289
Uniprot Name
Protein-tyrosine kinase 2-beta
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
Substrate
Inhibitor
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 un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. 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]
  2. Rozman B: Clinical pharmacokinetics of leflunomide. Clin Pharmacokinet. 2002;41(6):421-30. doi: 10.2165/00003088-200241060-00003. [PubMed:12074690]
  3. Leflunomide FDA label [File]
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 un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
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 fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
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]

Drug created on June 13, 2005 07:24 / Updated on December 13, 2018 08:10