Chemical: Drug
leflunomide

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PharmGKB contains no Clinical Variants that meet the highest level of criteria.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the page.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

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The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page.

Links in the "Gene" column lead to PharmGKB Gene Pages.

List of all variant annotations for leflunomide

Gene ? Variant?
(147)
Alternate Names ? Chemicals ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available No Clinical Annotations available VA
rs1256049 NC_000014.8:g.64724051C>T, NC_000014.9:g.64257333C>T, NG_011535.1:g.86218G>A, NM_001040275.1:c.984G>A, NM_001214902.1:c.984G>A, NM_001214903.1:c.984G>A, NM_001271876.1:c.984G>A, NM_001271877.1:c.952+3116G>A, NM_001291712.1:c.984G>A, NM_001291723.1:c.984G>A, NM_001437.2:c.984G>A, NP_001035365.1:p.Val328=, NP_001201831.1:p.Val328=, NP_001201832.1:p.Val328=, NP_001258805.1:p.Val328=, NP_001278641.1:p.Val328=, NP_001278652.1:p.Val328=, NP_001428.1:p.Val328=, NR_073496.1:n.1695+3116G>A, NR_073497.1:n.952G>A, NR_073505.1:n.1727G>A, XM_011536545.1:c.984G>A, XM_011536546.1:c.984G>A, XP_011534847.1:p.Val328=, XP_011534848.1:p.Val328=, rs17225976, rs386524925, rs60892953
C > -
C > T
SNP
V328V
No VIP available No Clinical Annotations available VA
rs12720461 NC_000015.10:g.74749010C>T, NC_000015.9:g.75041351C>T, NG_008431.1:g.31469C>T, NM_000761.3:c.-10+113C>T, NM_000761.4:c.-10+113C>T, rs59459319
C > T
SNP
No VIP available No Clinical Annotations available VA
rs2069526 NC_000015.10:g.74749000T>G, NC_000015.9:g.75041341T>G, NG_008431.1:g.31459T>G, NM_000761.3:c.-10+103T>G, NM_000761.4:c.-10+103T>G, rs17861148, rs57601484, rs61709032
T > G
SNP
No VIP available CA VA
rs2234693 NC_000006.11:g.152163335T>C, NC_000006.12:g.151842200T>C, NG_008493.1:g.156705T>C, NM_000125.3:c.453-397T>C, NM_001122740.1:c.453-397T>C, NM_001122741.1:c.453-397T>C, NM_001122742.1:c.453-397T>C, NM_001291230.1:c.453-397T>C, NM_001291241.1:c.453-397T>C, XM_005266856.1:c.453-397T>C, XM_005266857.1:c.453-397T>C, XM_006715374.2:c.453-397T>C, XM_006715375.2:c.-67-397T>C, XM_011535543.1:c.453-397T>C, XM_011535544.1:c.453-397T>C, XM_011535545.1:c.453-397T>C, XM_011535546.1:c.453-397T>C, XM_011535547.1:c.453-397T>C, XM_011535548.1:c.-67-397T>C, rs4134641, rs60769286
T > C
SNP
No VIP available No Clinical Annotations available VA
rs2476601 NC_000001.10:g.114377568A=, NC_000001.10:g.114377568A>G, NC_000001.11:g.113834946A=, NC_000001.11:g.113834946A>G, NG_011432.1:g.41808C=, NG_011432.1:g.41808C>T, NM_001193431.2:c.1858C=, NM_001193431.2:c.1858C>T, NM_001308297.1:c.1786C=, NM_001308297.1:c.1786C>T, NM_012411.5:c.1693C=, NM_012411.5:c.1693C>T, NM_015967.5:c.1858C>T, NM_015967.6:c.1858C=, NM_015967.6:c.1858C>T, NP_001180360.1:p.Arg620=, NP_001180360.1:p.Arg620Trp, NP_001295226.1:p.Arg596=, NP_001295226.1:p.Arg596Trp, NP_036543.4:p.Arg565=, NP_036543.4:p.Arg565Trp, NP_057051.3:p.Arg620=, NP_057051.3:p.Arg620Trp, NR_125965.1:n.414+19474A>G, NR_125965.1:n.414+19474G>A, XM_005270738.1:c.1786T=, XM_005270738.1:c.1786T>C, XM_005270738.2:c.1786T=, XM_005270738.2:c.1786T>C, XM_011541221.1:c.1780T=, XM_011541221.1:c.1780T>C, XM_011541222.1:c.1858T=, XM_011541222.1:c.1858T>C, XM_011541223.1:c.1858T=, XM_011541223.1:c.1858T>C, XM_011541224.1:c.1414T=, XM_011541224.1:c.1414T>C, XM_011541225.1:c.1786T=, XM_011541225.1:c.1786T>C, XP_005270795.1:p.Trp596=, XP_005270795.1:p.Trp596Arg, XP_011539523.1:p.Trp594=, XP_011539523.1:p.Trp594Arg, XP_011539524.1:p.Trp620=, XP_011539524.1:p.Trp620Arg, XP_011539525.1:p.Trp620=, XP_011539525.1:p.Trp620Arg, XP_011539526.1:p.Trp472=, XP_011539526.1:p.Trp472Arg, XP_011539527.1:p.Trp596=, XP_011539527.1:p.Trp596Arg, rs117063937, rs52834763, rs60104027
A > G
SNP
R620W
No VIP available CA VA
rs3213422 NC_000016.10:g.72008783A>C, NC_000016.9:g.72042682A>C, NG_016271.1:g.5040A>C, NM_001361.4:c.19A>C, NP_001352.2:p.Lys7Gln, XM_005255827.1:c.-428A>C, XM_005255827.2:c.-428A>C, rs17665243, rs386580989, rs52805696, rs61491058
A > C
SNP
K7Q
No VIP available No Clinical Annotations available VA
rs4244285 NC_000010.10:g.96541616G>A, NC_000010.11:g.94781859G>A, NG_008384.2:g.24154G>A, NM_000769.1:c.681G>A, NM_000769.2:c.681G>A, NP_000760.1:p.Pro227=, rs116940633, rs17879456, rs60361278
G > A
SNP
P227P
No VIP available No Clinical Annotations available VA
rs4986938 NC_000014.8:g.64699816C>T, NC_000014.9:g.64233098C>T, NG_011535.1:g.110453G>A, NM_001040275.1:c.1406+1872G>A, NM_001214902.1:c.1406+1872G>A, NM_001271876.1:c.1406+1872G>A, NM_001271877.1:c.*39G>A, NM_001291712.1:c.1406+1872G>A, NM_001291723.1:c.1406+1872G>A, NM_001437.2:c.*39G>A, NR_073496.1:n.2010+1872G>A, NR_073497.1:n.1600G>A, NR_073505.1:n.2149+1872G>A, XM_011536545.1:c.1406+1872G>A, XM_011536546.1:c.*39G>A, rs17766687, rs386597008
C > -
C > T
SNP
No VIP available CA VA
rs762551 NC_000015.10:g.74749576C>A, NC_000015.9:g.75041917C>A, NG_008431.1:g.32035C>A, NM_000761.3:c.-9-154C>A, NM_000761.4:c.-9-154C>A, rs17861151, rs57172993
C > A
SNP
No VIP available CA VA
rs9340799 NC_000006.11:g.152163381A>G, NC_000006.12:g.151842246A>G, NG_008493.1:g.156751A>G, NM_000125.3:c.453-351A>G, NM_001122740.1:c.453-351A>G, NM_001122741.1:c.453-351A>G, NM_001122742.1:c.453-351A>G, NM_001291230.1:c.453-351A>G, NM_001291241.1:c.453-351A>G, XM_005266856.1:c.453-351A>G, XM_005266857.1:c.453-351A>G, XM_006715374.2:c.453-351A>G, XM_006715375.2:c.-67-351A>G, XM_011535543.1:c.453-351A>G, XM_011535544.1:c.453-351A>G, XM_011535545.1:c.453-351A>G, XM_011535546.1:c.453-351A>G, XM_011535547.1:c.453-351A>G, XM_011535548.1:c.-67-351A>G, rs17208058, rs59875577
A > G
SNP
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 147

Overview

Generic Names
  • Leflunomidum [INN-Latin]
  • Lefunomide [INN-Spanish]
  • leflunomide
Trade Names
  • Arava
Brand Mixture Names

PharmGKB Accession Id

PA450192

Type(s):

Drug

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.

Source: Drug Bank

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.

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

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 alpha/beta-barrel domain containing the active site and an alpha-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-beta (TGF-beta). 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.

Source: Drug Bank

Pharmacology

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.

Source: Drug Bank

Food Interaction

Take without regard to meals.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Primarily hepatic. Leflunomide is converted to its active form following oral intake.

Source: Drug Bank

Protein Binding

>99.3%

Source: Drug Bank

Absorption

Well absorbed, peak plasma concentrations appear 6-12 hours after dosing

Source: Drug Bank

Half-Life

2 weeks

Source: Drug Bank

Toxicity

LD 50=100-250 mg/kg (acute oral toxicity)

Source: Drug Bank

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.

Source: Drug Bank

Volume of Distribution

  • 0.13 L/kg

Source: Drug Bank

Chemical Properties

Chemical Formula

C12H9F3N2O2

Source: Drug Bank

Isomeric SMILES

Cc1c(cno1)C(=O)Nc2ccc(cc2)C(F)(F)F

Source: OpenEye

Canonical SMILES

CC1=C(C=NO1)C(=O)NC1=CC=C(C=C1)C(F)(F)F

Source: Drug Bank

Average Molecular Weight

270.2073

Source: Drug Bank

Monoisotopic Molecular Weight

270.061612157

Source: Drug Bank

SMILES

CC1=C(C=NO1)C(=O)NC1=CC=C(C=C1)C(F)(F)F

Source: Drug Bank

InChI String

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)

Source: Drug Bank

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

Drug Targets

Gene Description
AHR (source: Drug Bank)
ALOX5 (source: Drug Bank)
DHODH (source: Drug Bank)

Drug Interactions

Interaction Description
leflunomide - acenocoumarol Leflunomide increases the anticoagulant effect (source: Drug Bank)
leflunomide - acenocoumarol Leflunomide may increase the anticoagulant effect of acenocoumarol. (source: Drug Bank)
leflunomide - anisindione Leflunomide may increase the anticoagulant effect of anisindione. (source: Drug Bank)
leflunomide - dicumarol Leflunomide increases the anticoagulant effect (source: Drug Bank)
leflunomide - dicumarol Leflunomide may increase the anticoagulant effect of dicumarol. (source: Drug Bank)
leflunomide - rifampin Rifampin increases the effect of leflunomide (source: Drug Bank)
leflunomide - rifampin Rifampin increases the effect of leflunomide (source: Drug Bank)
leflunomide - warfarin Leflunomide increases the anticoagulant effect (source: Drug Bank)
leflunomide - warfarin Leflunomide may increase the anticoagulant effect of warfarin. (source: Drug Bank)
rifampin - leflunomide Rifampin increases the effect of leflunomide (source: Drug Bank)
rifampin - leflunomide Rifampin increases the effect of leflunomide (source: Drug Bank)
vincristine - leflunomide Vincristine may increase the adverse/toxic effects of Leflunomide. This may increase the risk of hematologic toxicities such as pancytopenia, agranulocytosis and thrombocytopenia. In patients receiving Vincristine, consider eliminating the loading dose of Leflunomide. Monitor for bone marrow suppression at least monthly during concomitant therapy. (source: Drug Bank)
vinorelbine - leflunomide Vinorelbine may increase the adverse/toxic effects of Leflunomide. This may increase the risk of hematologic toxicities such as pancytopenia, agranulocytosis and thrombocytopenia. In patients receiving Vinorelbine, consider eliminating the loading dose of Leflunomide. Monitor for bone marrow suppression at least monthly during concomitant therapy. (source: Drug Bank)

Curated Information ?

Relationships from National Drug File - Reference Terminology (NDF-RT)

May Treat
Contraindicated With

Publications related to leflunomide: 9

No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
The rheumatoid arthritis susceptibility polymorphism PTPN22 C1858T is not associated with leflunomide response or toxicity. Journal of clinical pharmacy and therapeutics. 2014. Hopkins A M, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Genetic polymorphisms affect efficacy and adverse drug reactions of DMARDs in rheumatoid arthritis. Pharmacogenetics and genomics. 2014. Zhang Ling Ling, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacogenetics of disease-modifying antirheumatic drugs in rheumatoid arthritis: towards personalized medicine. Pharmacogenomics. 2013. Umićević Mirkov Maša, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
The effect of ESR1 and ESR2 gene polymorphisms on the outcome of rheumatoid arthritis treatment with leflunomide. Pharmacogenomics. 2011. Dziedziejko Violetta, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Effective global drug development strategy for obtaining regulatory approval in Japan in the context of ethnicity-related drug response factors. Clinical pharmacology and therapeutics. 2010. Ichimaru K, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Investigation of the influence of CYP1A2 and CYP2C19 genetic polymorphism on 2-Cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide (A77 1726) pharmacokinetics in leflunomide-treated patients with rheumatoid arthritis. Drug metabolism and disposition: the biological fate of chemicals. 2009. Bohanec Grabar Petra, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
The effect of exon (19C>A) dihydroorotate dehydrogenase gene polymorphism on rheumatoid arthritis treatment with leflunomide. Pharmacogenomics. 2009. Pawlik Andrzej, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients. European journal of clinical pharmacology. 2008. Bohanec Grabar Petra, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Idiosyncratic drug hepatotoxicity. Nature reviews. Drug discovery. 2005. Kaplowitz Neil. PubMed

LinkOuts

Web Resource:
Wikipedia
National Drug Code Directory:
0555-0351-01
DrugBank:
DB01097
ChEBI:
6402
KEGG Compound:
C07905
KEGG Drug:
D00749
PubChem Compound:
3899
PubChem Substance:
191162
46506013
Drugs Product Database (DPD):
2261278
ChemSpider:
3762
Therapeutic Targets Database:
DAP000636
FDA Drug Label at DailyMed:
151ffcf4-e503-4954-af7c-93d0a4f9f80e

Clinical Trials

These are trials that mention leflunomide and are related to either pharmacogenetics or pharmacogenomics.

No trials loaded.

NURSA Datasets

provided by nursa.org

No NURSA datasets available.

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Sources for PharmGKB drug information: DrugBank, PubChem.