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

Similar Structures

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

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
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Arava	Tablet, film coated	20 mg/1	Oral	bryant ranch prepack	1998-09-10	Not applicable
Arava	Tablet, film coated	20 mg	Oral	Sanofi Aventis Deutschland Gmb H	1999-09-02	Not applicable
Arava	Tablet, film coated	10 mg	Oral	Sanofi Aventis Deutschland Gmb H	1999-09-02	Not applicable
Arava	Tablet, film coated	20 mg/1	Oral	sanofi-aventis U.S. LLC	1998-09-10	Not applicable
Arava	Tablet, film coated	10 mg/1	Oral	Physicians Total Care, Inc.	2003-08-25	2011-06-30
Arava	Tablet, film coated	10 mg	Oral	Sanofi Aventis Deutschland Gmb H	1999-09-02	Not applicable
Arava	Tablet, film coated	10 mg/1	Oral	sanofi-aventis U.S. LLC	1998-09-10	Not applicable
Arava	Tablet, film coated	20 mg	Oral	Sanofi Aventis Deutschland Gmb H	1999-09-02	Not applicable
Arava	Tablet, film coated	20 mg	Oral	Sanofi Aventis Deutschland Gmb H	1999-09-02	Not applicable
Arava	Tablet, film coated	10 mg	Oral	Sanofi Aventis Deutschland Gmb H	1999-09-02	Not applicable

Additional Data Available

Application Number

A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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Product Code

A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
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Accel-leflunomide	Tablet		Oral	Accel Pharma Inc	2019-09-19	Not applicable
Accel-leflunomide	Tablet		Oral	Accel Pharma Inc	2019-09-19	Not applicable
Apo-leflunomide	Tablet		Oral	Apotex Corporation	2004-09-14	Not applicable
Apo-leflunomide	Tablet		Oral	Apotex Corporation	2004-09-14	Not applicable
Dom-leflunomide	Tablet		Oral	Dominion Pharmacal	Not applicable	Not applicable
Dom-leflunomide	Tablet		Oral	Dominion Pharmacal	Not applicable	Not applicable
Leflunomide	Tablet	20 mg/1	Oral	Dispensing Solutions, Inc.	2009-10-29	Not applicable
Leflunomide	Tablet	10 mg/1	Oral	Trigen Laboratories, LLC	2011-05-06	2019-12-31
Leflunomide	Tablet, film coated	20 mg/1	Oral	Barr Laboratories	2005-09-14	2011-09-30
Leflunomide	Tablet	20 mg/1	Oral	KVK-Tech, Inc.	2019-06-03	Not applicable

Additional Data Available

Application Number

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Product Code

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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.

Target	Actions	Organism
ADihydroorotate dehydrogenase (quinone), mitochondrial	inhibitor	Humans
UAryl hydrocarbon receptor	agonist	Humans
UProtein-tyrosine kinase 2-beta	antagonist	Humans

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Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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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.

Leflunomide
A771726

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/Enzyme	Allele name	Genotype(s)	Defining Change(s)	Type(s)	Description	Details
Cytochrome P450 1A2	---	(C;C)	C allele	ADR Directly Studied	The presence of this genotype in CYP1A2 may be associated with an increased risk of drug-related toxicity from leflunomide therapy.	Details

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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(R)-warfarin	The serum concentration of (R)-warfarin can be decreased when it is combined with Leflunomide.
(S)-Warfarin	The metabolism of (S)-Warfarin can be decreased when combined with Leflunomide.
2-Methoxyethanol	The risk or severity of adverse effects can be increased when 2-Methoxyethanol is combined with Leflunomide.
4-hydroxycoumarin	The therapeutic efficacy of 4-hydroxycoumarin can be increased when used in combination with Leflunomide.
6-O-benzylguanine	The serum concentration of 6-O-benzylguanine can be decreased when it is combined with Leflunomide.
8-azaguanine	The serum concentration of 8-azaguanine can be decreased when it is combined with Leflunomide.
8-chlorotheophylline	The serum concentration of 8-chlorotheophylline can be decreased when it is combined with Leflunomide.
9-(N-methyl-L-isoleucine)-cyclosporin A	The risk or severity of adverse effects can be increased when 9-(N-methyl-L-isoleucine)-cyclosporin A is combined with Leflunomide.
9-Deazaguanine	The serum concentration of 9-Deazaguanine can be decreased when it is combined with Leflunomide.
9-Methylguanine	The serum concentration of 9-Methylguanine can be decreased when it is combined with Leflunomide.

Additional Data Available

Extended Description

Extended description of the mechanism of action and particular properties of each drug interaction.

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Severity

A severity rating for each drug interaction, from minor to major.

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Evidence Level

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Action

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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

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]
Li EK, Tam LS, Tomlinson B: Leflunomide in the treatment of rheumatoid arthritis. Clin Ther. 2004 Apr;26(4):447-59. [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: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:11053058]
Reitzik M, Lownie JF: Familial polyostotic fibrous dysplasia. Oral Surg Oral Med Oral Pathol. 1975 Dec;40(6):769-74. [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: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:10878295]
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

Phase	Status	Purpose	Conditions	Count
1	Completed	Not Available	Healthy Volunteers	2
1	Completed	Not Available	To Determine the Bioequivalence Study Under Fasting	1
1	Completed	Other	To Determine Bioequivalence Under Fed Conditions	1
1	Completed	Treatment	Gliomas / Sarcomas	1
1	Completed	Treatment	Human Immunodeficiency Virus (HIV) Infections	1
1	Completed	Treatment	Psoriatic Arthritis / Rheumatoid Arthritis	1
1	Not Yet Recruiting	Treatment	Chronic Graft Versus Host Disease / Steroid Refractory Graft Versus Host Disease	1
1	Terminated	Treatment	Melanoma	1
1, 2	Active Not Recruiting	Treatment	Recurrent Plasma Cell Myeloma / Refractory Plasma Cell Myeloma	1
1, 2	Recruiting	Treatment	Breast Diseases / Metastatic Triple Negative Breast Cancer / Neoplasms, Breast	1
2	Completed	Treatment	Adult-Onset Still's Disease	1
2	Completed	Treatment	Brain and Central Nervous System Tumors	1
2	Completed	Treatment	Rheumatoid Arthritis	1
2	Completed	Treatment	Systemic Lupus Erythematosus (SLE)	1
2	Completed	Treatment	Uveitis	1
2	Recruiting	Treatment	Henoch-Schoenlein Purpura Nephritis	1
2	Terminated	Prevention	Viral sepsis / Viruria	1
2	Unknown Status	Treatment	Bullous Pemphigoid (BP)	1
2	Withdrawn	Treatment	Smoldering Plasma Cell Myeloma	1
2	Withdrawn	Treatment	Systemic Lupus Erythematosus (SLE)	1
2, 3	Completed	Treatment	Nephritis, Lupus	1
2, 3	Completed	Treatment	Prostate Cancer	1
3	Completed	Treatment	Brain and Central Nervous System Tumors	1
3	Completed	Treatment	Rheumatoid Arthritis	7
3	Recruiting	Treatment	Myasthenia Gravis	1
3	Recruiting	Treatment	Polymyalgia Rheumatica	1
3	Terminated	Treatment	Nephritis, Lupus	1
3	Terminated	Treatment	Rheumatoid Arthritis	2
4	Completed	Treatment	Immunoglobulin G4 Related Sclerosing Disease	1
4	Completed	Treatment	Rheumatoid Arthritis	7
4	Enrolling by Invitation	Basic Science	Rheumatoid Arthritis	1
4	Not Yet Recruiting	Treatment	IgA Glomerulonephritis / Renal Insufficiency,Chronic	1
4	Not Yet Recruiting	Treatment	Psoriatic Arthritis	2
4	Recruiting	Treatment	Rheumatoid Arthritis	1
4	Terminated	Treatment	Rheumatoid Arthritis	1
4	Unknown Status	Treatment	Juvenile Idiopathic Arthritis (JIA)	1
4	Unknown Status	Treatment	Rheumatoid Arthritis	1
Not Available	Active Not Recruiting	Not Available	Rheumatoid Arthritis / The Polymorphisms Associated With Efficacy or Adverse Reactions to the Drug	1
Not Available	Completed	Basic Science	Rheumatoid Arthritis	1
Not Available	Completed	Treatment	Rheumatoid Arthritis	1
Not Available	Recruiting	Not Available	Mechanisms, Defense / Outcomes / Pregnancy Related / Takayasu's Disease / Treatment Refusal	1
Not Available	Recruiting	Treatment	Autoimmune Diseases	1
Not Available	Recruiting	Treatment	Lupus / Nephritis	1
Not Available	Recruiting	Treatment	Takayasu's Disease	1
Not Available	Unknown Status	Treatment	BK Virus Infection / Terminal Renal Failure	1
Not Available	Unknown Status	Treatment	Rheumatoid Arthritis	1

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

Form	Route	Strength
Tablet, film coated	Oral	10 mg
Tablet, film coated	Oral	100 mg/1
Tablet, film coated	Oral	100 mg
Tablet, film coated	Oral	20 mg
Tablet	Oral
Tablet	Oral	10 mg
Tablet	Oral	10 mg/1
Tablet	Oral	20 mg/1
Tablet	Oral	20 mg
Tablet, film coated	Oral	10 mg/1
Tablet, film coated	Oral	20 mg/1
Tablet, film coated	Oral	15 mg

Prices

Unit description	Cost	Unit
Arava 10 mg tablet	24.76USD	tablet
Arava 20 mg tablet	24.76USD	tablet
Leflunomide 10 mg tablet	16.75USD	tablet
Leflunomide 20 mg tablet	16.75USD	tablet

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	165-166 °C	Not Available
water solubility	21 mg/L (poorly soluble)	Not Available
logP	2.8	Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0844 mg/mL	ALOGPS
logP	2.52	ALOGPS
logP	2.51	ChemAxon
logS	-3.5	ALOGPS
pKa (Strongest Acidic)	10.41	ChemAxon
pKa (Strongest Basic)	-0.45	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	2	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	55.13 Å²	ChemAxon
Rotatable Bond Count	3	ChemAxon
Refractivity	64.16 m³·mol^-1	ChemAxon
Polarizability	23.11 Å³	ChemAxon
Number of Rings	2	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET features

Property	Value	Probability
Human Intestinal Absorption	+	1.0
Blood Brain Barrier	+	0.9949
Caco-2 permeable	+	0.5069
P-glycoprotein substrate	Non-substrate	0.909
P-glycoprotein inhibitor I	Non-inhibitor	0.7822
P-glycoprotein inhibitor II	Non-inhibitor	0.8889
Renal organic cation transporter	Non-inhibitor	0.9154
CYP450 2C9 substrate	Non-substrate	0.8548
CYP450 2D6 substrate	Non-substrate	0.9116
CYP450 3A4 substrate	Non-substrate	0.5211
CYP450 1A2 substrate	Inhibitor	0.9189
CYP450 2C9 inhibitor	Non-inhibitor	0.9071
CYP450 2D6 inhibitor	Non-inhibitor	0.9231
CYP450 2C19 inhibitor	Non-inhibitor	0.9026
CYP450 3A4 inhibitor	Non-inhibitor	0.5117
CYP450 inhibitory promiscuity	High CYP Inhibitory Promiscuity	0.5622
Ames test	Non AMES toxic	0.5504
Carcinogenicity	Non-carcinogens	0.7067
Biodegradation	Not ready biodegradable	0.9836
Rat acute toxicity	3.0297 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9879
hERG inhibition (predictor II)	Non-inhibitor	0.9068

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	Not Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
LC-MS/MS Spectrum - LC-ESI-qTof , Positive	LC-MS/MS	Not Available
LC-MS/MS Spectrum - LC-ESI-qTof , Positive	LC-MS/MS	Not Available
MS/MS Spectrum - , positive	LC-MS/MS	splash10-00di-0390000000-1ac4065d1ef245442a16
MS/MS Spectrum - , positive	LC-MS/MS	splash10-03di-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

Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	10000	N/A	N/A	9873513
IC 50 (nM)	13000	N/A	N/A	9719606

Details1. Dihydroorotate dehydrogenase (quinone), mitochondrial

Kind: Protein
Organism: Humans
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

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
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]
Prakash A, Jarvis B: Leflunomide: a review of its use in active rheumatoid arthritis. Drugs. 1999 Dec;58(6):1137-64. [PubMed:10651393]
Li EK, Tam LS, Tomlinson B: Leflunomide in the treatment of rheumatoid arthritis. Clin Ther. 2004 Apr;26(4):447-59. [PubMed:15189743]
Wozel G, Pfeiffer C: [Leflunomide--a new drug for pharmacological immunomodulation]. Hautarzt. 2002 May;53(5):309-15. [PubMed:12063741]
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]
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]
Reitzik M, Lownie JF: Familial polyostotic fibrous dysplasia. Oral Surg Oral Med Oral Pathol. 1975 Dec;40(6):769-74. [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: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:10878295]
Fox RI: Mechanism of action of leflunomide in rheumatoid arthritis. J Rheumatol Suppl. 1998 Jul;53:20-6. [PubMed:9666414]
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]

Details2. Aryl hydrocarbon receptor

Kind: Protein
Organism: Humans
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

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]
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]

Details3. Protein-tyrosine kinase 2-beta

Kind: Protein
Organism: Humans
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

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]
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]
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

Details1. Cytochrome P450 2C9

Kind: Protein
Organism: Humans
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

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]
Rozman B: Clinical pharmacokinetics of leflunomide. Clin Pharmacokinet. 2002;41(6):421-30. doi: 10.2165/00003088-200241060-00003. [PubMed:12074690]
Leflunomide FDA label [File]

Details2. Cytochrome P450 1A2

Kind: Protein
Organism: Humans
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

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]
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

Details1. ATP-binding cassette sub-family G member 2

Kind: Protein
Organism: Humans
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

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 January 26, 2020 14:39

Leflunomide

Identification

Structure for Leflunomide (DB01097)

Pharmacology

Interactions

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Taxonomy

Targets

References

References

References

Enzymes

References

References

Transporters

References