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Identification
NameTeriflunomide
Accession NumberDB08880
TypeSmall Molecule
GroupsApproved
Description

Teriflunomide is the active metabolite of leflunomide, and it acts as an immunomodulatory agent by inhibiting pyrimidine synthesis. It is marketed under the name Aubagio® and is indicated for the treatment of multiple sclerosis, specifically relapsing forms. The FDA label states an important warning about the risk of hepatoxicity and teratogenicity for patients using teriflunomide.

Structure
Thumb
Synonyms
(Z)-2-Cyano-alpha,alpha,alpha-trifluoro-3-hydroxy-P-crotonotoluidide
a 77-1726
a 771726
Aubagio
HMR 1726
HMR1726
Teriflunomida
Teriflunomidum
External Identifiers
  • A-771726
  • HMR1726
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Aubagiotablet, film coated14 mg/1oralGenzyme Corp.2013-05-01Not applicableUs
Aubagiotablet14 mgoralGenzyme Canada A Division Of Sanofi Aventis Canada Inc2013-11-15Not applicableCanada
Aubagiotablet, film coated7 mg/1oralGenzyme Corp.2013-05-01Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII1C058IKG3B
CAS number163451-81-8
WeightNot Available
Chemical FormulaNot Available
InChI KeyNot Available
InChINot Available
IUPAC NameNot Available
SMILESNot Available
Taxonomy
ClassificationNot classified
Pharmacology
IndicationUsed in the treatment of relapsing forms of multiple sclerosis (MS).
PharmacodynamicsTeriflunomide is an immunomodulatory agent that decreases the amount of activated CNS lymphocytes, which results in anti-inflammatory and antiproliferative effects.
Mechanism of actionThe exact mechanism by which teriflunomide acts in MS is not known. What is known is that teriflunomide prevents pyrimidine synthesis by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase, and this may be involved in its immunomodulatory effect in MS.
Related Articles
AbsorptionAfter oral administration of teriflunomide, maximum plasma concentrations are reached, on average, in 1-4 hours.
Volume of distribution

After a single intravenous dose, the volume of distribution is 11 L.

Protein bindingTeriflunomide is extensively plasma protein bound(>99%).
Metabolism

Teriflunomide mainly undergoes hydrolyis to minor metabolites. Other minor metabolic pathways include oxidation, N-acetylation and sulfate conjugation. Teriflunomide is not metabolized by CYP450 or flavin monoamine oxidase.

Route of eliminationTeriflunomide is eliminated unchanged and mainly through bile. Specifically 37.5% is eliminated in the feces and 22.6% in urine.
Half lifeThe median half-life is 18 to 19 days.
Clearance

After a single IV dose, teriflunomide has a total body clearance of 30.5 mL/h.

ToxicityTeriflunomide is contraindicated in pregnant women or women of childbearing age due to the risk of teratogenicity. Teriflunomide is also contraindicated in severe hepatic impairment due to reports of hepatotoxicity, hepatic failure, and death.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal AbsorptionNot AvailableNot Available
Blood Brain BarrierNot AvailableNot Available
Caco-2 permeableNot AvailableNot Available
P-glycoprotein substrateNot AvailableNot Available
P-glycoprotein inhibitor INot AvailableNot Available
P-glycoprotein inhibitor IINot AvailableNot Available
Renal organic cation transporterNot AvailableNot Available
CYP450 2C9 substrateNot AvailableNot Available
CYP450 2D6 substrateNot AvailableNot Available
CYP450 3A4 substrateNot AvailableNot Available
CYP450 1A2 substrateNot AvailableNot Available
CYP450 2C9 inhibitorNot AvailableNot Available
CYP450 2D6 inhibitorNot AvailableNot Available
CYP450 2C19 inhibitorNot AvailableNot Available
CYP450 3A4 inhibitorNot AvailableNot Available
CYP450 inhibitory promiscuityNot AvailableNot Available
Ames testNot AvailableNot Available
CarcinogenicityNot AvailableNot Available
BiodegradationNot AvailableNot Available
Rat acute toxicityNot AvailableNot applicable
hERG inhibition (predictor I)Not AvailableNot Available
hERG inhibition (predictor II)Not AvailableNot Available
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tabletoral14 mg
Tablet, film coatedoral14 mg/1
Tablet, film coatedoral7 mg/1
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6794410 No2002-04-152022-04-15Us
US8802735 No2010-09-142030-09-14Us
US9186346 No2014-02-042034-02-04Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubilitySoluble in DMSO (practically insoluble in water).From FDA label.
Predicted PropertiesNot Available
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
References
Synthesis Reference

Keshav Deo, Samir Patel, Snehal Dhol, Sunil Sanghani, Vishal Ray, " PROCESS FOR PREPARING TERIFLUNOMIDE." U.S. Patent US20110092727, issued April 21, 2011.

US20110092727
General References
  1. O'Connor PW, Li D, Freedman MS, Bar-Or A, Rice GP, Confavreux C, Paty DW, Stewart JA, Scheyer R: A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology. 2006 Mar 28;66(6):894-900. [PubMed:16567708 ]
  2. Tallantyre E, Evangelou N, Constantinescu CS: Spotlight on teriflunomide. Int MS J. 2008 Jun;15(2):62-8. [PubMed:18782502 ]
External Links
ATC CodesL04AA31
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (527 KB)
MSDSDownload (124 KB)
Interactions
Drug Interactions
Drug
AcenocoumarolThe serum concentration of Acenocoumarol can be decreased when it is combined with Teriflunomide.
Activated charcoalThe serum concentration of Teriflunomide can be decreased when it is combined with Activated charcoal.
Aminohippuric acidThe serum concentration of Aminohippurate can be increased when it is combined with Teriflunomide.
AminophyllineThe serum concentration of Aminophylline can be decreased when it is combined with Teriflunomide.
AmodiaquineThe serum concentration of Amodiaquine can be increased when it is combined with Teriflunomide.
AsenapineThe serum concentration of Asenapine can be decreased when it is combined with Teriflunomide.
AtorvastatinThe serum concentration of Atorvastatin can be increased when it is combined with Teriflunomide.
Benzathine benzylpenicillinThe serum concentration of Benzathine benzylpenicillin can be increased when it is combined with Teriflunomide.
BetaxololThe serum concentration of Betaxolol can be decreased when it is combined with Teriflunomide.
BortezomibThe serum concentration of Bortezomib can be decreased when it is combined with Teriflunomide.
BosentanThe serum concentration of Bosentan can be increased when it is combined with Teriflunomide.
CaffeineThe serum concentration of Caffeine can be decreased when it is combined with Teriflunomide.
CefaclorThe serum concentration of Cefaclor can be increased when it is combined with Teriflunomide.
CholestyramineThe serum concentration of Teriflunomide can be decreased when it is combined with Cholestyramine.
CimetidineThe serum concentration of Cimetidine can be increased when it is combined with Teriflunomide.
CiprofloxacinThe serum concentration of Ciprofloxacin can be increased when it is combined with Teriflunomide.
ClomipramineThe serum concentration of Clomipramine can be decreased when it is combined with Teriflunomide.
ClozapineThe serum concentration of Clozapine can be decreased when it is combined with Teriflunomide.
ColesevelamThe serum concentration of Teriflunomide can be decreased when it is combined with Colesevelam.
ColestipolThe serum concentration of Teriflunomide can be decreased when it is combined with Colestipol.
DacarbazineThe serum concentration of Dacarbazine can be decreased when it is combined with Teriflunomide.
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Teriflunomide.
DuloxetineThe serum concentration of Duloxetine can be decreased when it is combined with Teriflunomide.
EluxadolineThe serum concentration of Eluxadoline can be increased when it is combined with Teriflunomide.
EmpagliflozinThe serum concentration of Empagliflozin can be increased when it is combined with Teriflunomide.
EstradiolThe serum concentration of Estradiol can be decreased when it is combined with Teriflunomide.
Estrone sulfateThe serum concentration of Estropipate can be decreased when it is combined with Teriflunomide.
EzetimibeThe serum concentration of Ezetimibe can be increased when it is combined with Teriflunomide.
FexofenadineThe serum concentration of Fexofenadine can be increased when it is combined with Teriflunomide.
FlutamideThe serum concentration of Flutamide can be decreased when it is combined with Teriflunomide.
FluvastatinThe serum concentration of Fluvastatin can be increased when it is combined with Teriflunomide.
FluvoxamineThe serum concentration of Fluvoxamine can be decreased when it is combined with Teriflunomide.
FurosemideThe serum concentration of Furosemide can be increased when it is combined with Teriflunomide.
GefitinibThe serum concentration of Gefitinib can be increased when it is combined with Teriflunomide.
IrinotecanThe serum concentration of Irinotecan can be increased when it is combined with Teriflunomide.
KetoprofenThe serum concentration of Ketoprofen can be increased when it is combined with Teriflunomide.
LeflunomideThe risk or severity of adverse effects can be increased when Leflunomide is combined with Teriflunomide.
LidocaineThe serum concentration of Lidocaine can be decreased when it is combined with Teriflunomide.
MethotrexateThe serum concentration of Methotrexate can be increased when it is combined with Teriflunomide.
MexiletineThe serum concentration of Mexiletine can be decreased when it is combined with Teriflunomide.
MirtazapineThe serum concentration of Mirtazapine can be decreased when it is combined with Teriflunomide.
MitoxantroneThe serum concentration of Mitoxantrone can be increased when it is combined with Teriflunomide.
Mycophenolate mofetilThe serum concentration of Mycophenolate mofetil can be increased when it is combined with Teriflunomide.
Mycophenolic acidThe serum concentration of Mycophenolic acid can be increased when it is combined with Teriflunomide.
NatalizumabThe risk or severity of adverse effects can be increased when Teriflunomide is combined with Natalizumab.
NateglinideThe serum concentration of Nateglinide can be increased when it is combined with Teriflunomide.
OlanzapineThe serum concentration of Olanzapine can be decreased when it is combined with Teriflunomide.
OlmesartanThe serum concentration of Olmesartan can be increased when it is combined with Teriflunomide.
PazopanibThe serum concentration of Pazopanib can be increased when it is combined with Teriflunomide.
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Teriflunomide.
PimozideThe serum concentration of Pimozide can be decreased when it is combined with Teriflunomide.
PitavastatinThe serum concentration of Pitavastatin can be increased when it is combined with Teriflunomide.
PomalidomideThe serum concentration of Pomalidomide can be decreased when it is combined with Teriflunomide.
PravastatinThe serum concentration of Pravastatin can be increased when it is combined with Teriflunomide.
Procaine benzylpenicillinThe serum concentration of Procaine benzylpenicillin can be increased when it is combined with Teriflunomide.
PropranololThe serum concentration of Propranolol can be decreased when it is combined with Teriflunomide.
RasagilineThe serum concentration of Rasagiline can be decreased when it is combined with Teriflunomide.
RepaglinideThe serum concentration of Repaglinide can be increased when it is combined with Teriflunomide.
RifampicinThe serum concentration of Rifampicin can be increased when it is combined with Teriflunomide.
RiluzoleThe serum concentration of Riluzole can be decreased when it is combined with Teriflunomide.
RiociguatThe serum concentration of Riociguat can be increased when it is combined with Teriflunomide.
RoflumilastRoflumilast may increase the immunosuppressive activities of Teriflunomide.
RopiniroleThe serum concentration of Ropinirole can be decreased when it is combined with Teriflunomide.
RosuvastatinThe serum concentration of Rosuvastatin can be increased when it is combined with Teriflunomide.
SimeprevirThe serum concentration of Simeprevir can be increased when it is combined with Teriflunomide.
SimvastatinThe serum concentration of Simvastatin can be increased when it is combined with Teriflunomide.
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Teriflunomide.
StiripentolThe serum concentration of Stiripentol can be decreased when it is combined with Teriflunomide.
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Teriflunomide.
TasimelteonThe serum concentration of Tasimelteon can be decreased when it is combined with Teriflunomide.
Taurocholic AcidThe serum concentration of Taurocholic Acid can be increased when it is combined with Teriflunomide.
TheophyllineThe serum concentration of Theophylline can be decreased when it is combined with Teriflunomide.
ThiothixeneThe serum concentration of Thiothixene can be decreased when it is combined with Teriflunomide.
TofacitinibTeriflunomide may increase the immunosuppressive activities of Tofacitinib.
TopotecanThe serum concentration of Topotecan can be increased when it is combined with Teriflunomide.
TorasemideThe serum concentration of Torasemide can be increased when it is combined with Teriflunomide.
TrastuzumabTrastuzumab may increase the neutropenic activities of Teriflunomide.
TrifluoperazineThe serum concentration of Trifluoperazine can be decreased when it is combined with Teriflunomide.
ValsartanThe serum concentration of Valsartan can be increased when it is combined with Teriflunomide.
WarfarinThe serum concentration of Warfarin can be decreased when it is combined with Teriflunomide.
ZidovudineThe serum concentration of Zidovudine can be increased when it is combined with Teriflunomide.
Food Interactions
  • Food does not affect teriflunomide pharmacokinetics, so take with or without food.

Targets

Kind
Protein
Organism
Human
Pharmacological action
unknown
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. Palmer AM: Teriflunomide, an inhibitor of dihydroorotate dehydrogenase for the potential oral treatment of multiple sclerosis. Curr Opin Investig Drugs. 2010 Nov;11(11):1313-23. [PubMed:21157651 ]
  2. Davis JP, Cain GA, Pitts WJ, Magolda RL, Copeland RA: The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase. Biochemistry. 1996 Jan 30;35(4):1270-3. [PubMed:8573583 ]

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 May 19, 2013 20:55 / Updated on July 29, 2016 01:53