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Identification
NameRiluzole
Accession NumberDB00740  (APRD00145)
TypeSmall Molecule
GroupsApproved, Investigational
Description

A glutamate antagonist (receptors, glutamate) used as an anticonvulsant (anticonvulsants) and to prolong the survival of patients with amyotrophic lateral sclerosis. Riluzole is marketed as Rilutek by Sanofi.

Structure
Thumb
Synonyms
Riluzol
Riluzole
Riluzolum
External Identifiers
  • PK 26124
  • RP 54274
  • RPR 202
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Mylan-riluzoletablet50 mgoralMylan Pharmaceuticals Ulc2012-10-23Not applicableCanada
Rilutektablet, film coated50 mg/1oralSanofi Aventis U.S. Llc1995-12-12Not applicableUs
Rilutektablet50 mg/1oralCovis Pharmaceuticals, Inc.2013-07-15Not applicableUs
Rilutektablet50 mgoralSanofi Aventis Canada Inc2000-10-26Not applicableCanada
Rilutektablet50 mg/1oralKAISER FOUNDATION HOSPITALS2014-01-20Not applicableUs
Riluzoletablet, film coated50 mg/1oralRising Pharmaceuticals, Inc.2013-05-15Not applicableUs
Riluzoletablet, film coated50 mg/1oralAv Kare, Inc.2014-01-08Not applicableUs
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo-riluzoletablet50 mgoralApotex Inc2012-09-25Not applicableCanada
Riluzoletablet50 mg/1oralAscend Laboratories, LLC2016-03-31Not applicableUs
Riluzoletablet, film coated50 mg/1oralGlobal Pharmaceuticals, Division of Impax Laboratories, Inc.2003-01-29Not applicableUs
Riluzoletablet, film coated50 mg/1oralGlenmark Pharmaceuticals Inc., Usa2013-06-18Not applicableUs
Riluzoletablet, film coated50 mg/1oralAmerican Health Packaging2015-03-31Not applicableUs
Riluzoletablet, film coated50 mg/1oralSun Pharmaceutical Industries Limited2013-06-18Not applicableUs
Riluzoletablet, film coated50 mg/1oralApotex Corp2013-06-18Not applicableUs
Riluzoletablet, film coated50 mg/1oralMylan Pharmaceuticals Inc.2013-07-22Not applicableUs
Riluzoletablet, film coated50 mg/1oralKAISER FOUNDATION HOSPITALS2014-05-14Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
FanizanActavis
LaidecSun Pro
LizolorolActavis
Lizorololratiopharm
RilustadSTADA
ScleficActavis
Xie Yi LiLunan Pharm
ZolerilisActavis
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Riluzole Hydrochloride
Thumb
  • InChI Key: QEAOELIJQRYJJS-UHFFFAOYSA-N
  • Monoisotopic Mass: 269.984145836
  • Average Mass: 270.659
DBSALT000679
Categories
UNII7LJ087RS6F
CAS number1744-22-5
WeightAverage: 234.198
Monoisotopic: 234.007468097
Chemical FormulaC8H5F3N2OS
InChI KeyInChIKey=FTALBRSUTCGOEG-UHFFFAOYSA-N
InChI
InChI=1S/C8H5F3N2OS/c9-8(10,11)14-4-1-2-5-6(3-4)15-7(12)13-5/h1-3H,(H2,12,13)
IUPAC Name
6-(trifluoromethoxy)-1,3-benzothiazol-2-amine
SMILES
NC1=NC2=C(S1)C=C(OC(F)(F)F)C=C2
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as benzothiazoles. These are organic compounds containing a benzene fused to a thiazole ring (a five-membered ring with four carbon atoms, one nitrogen atom and one sulfur atom).
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassBenzothiazoles
Sub ClassNot Available
Direct ParentBenzothiazoles
Alternative Parents
Substituents
  • 1,3-benzothiazole
  • Benzenoid
  • Primary aromatic amine
  • Heteroaromatic compound
  • Thiazole
  • Azole
  • Trihalomethane
  • Azacycle
  • Halomethane
  • Hydrocarbon derivative
  • Primary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organohalogen compound
  • Amine
  • Alkyl halide
  • Alkyl fluoride
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor the treatment of amyotrophic lateral sclerosis (ALS, Lou Gehrig's Disease)
PharmacodynamicsRiluzole, a member of the benzothiazole class, is indicated for the treatment of patients with amyotrophic lateral sclerosis (ALS). Riluzole extends survival and/or time to tracheostomy. It is also neuroprotective in various in vivo experimental models of neuronal injury involving excitotoxic mechanisms. The etiology and pathogenesis of amyotrophic lateral sclerosis (ALS) are not known, although a number of hypotheses have been advanced. One hypothesis is that motor neurons, made vulnerable through either genetic predisposition or environmental factors, are injured by glutamate. In some cases of familial ALS the enzyme superoxide dismutase has been found to be defective.
Mechanism of actionThe mode of action of riluzole is unknown. Its pharmacological properties include the following, some of which may be related to its effect: 1) an inhibitory effect on glutamate release (activation of glutamate reuptake), 2) inactivation of voltage-dependent sodium channels, and 3) ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors.
Related Articles
AbsorptionRiluzole is well-absorbed (approximately 90%), with average absolute oral bioavailability of about 60% (CV=30%). A high fat meal decreases absorption, reducing AUC by about 20% and peak blood levels by about 45%.
Volume of distributionNot Available
Protein binding96% bound to plasma proteins, mainly to albumin and lipoprotein over the clinical concentration range.
Metabolism

Riluzole is extensively metabolized to six major and a number of minor metabolites, which have not all been identified to date. Metabolism is mostly hepatic, consisting of cytochrome P450–dependent hydroxylation and glucuronidation. CYP1A2 is the primary isozyme involved in N-hydroxylation; CYP2D6, CYP2C19, CYP3A4, and CYP2E1 are considered unlikely to contribute significantly to riluzole metabolism in humans.

Route of eliminationNot Available
Half lifeThe mean elimination half-life of riluzole is 12 hours (CV=35%) after repeated doses.
ClearanceNot Available
ToxicityNot Available
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 Absorption+0.995
Blood Brain Barrier+0.9799
Caco-2 permeable-0.5377
P-glycoprotein substrateNon-substrate0.8045
P-glycoprotein inhibitor INon-inhibitor0.8245
P-glycoprotein inhibitor IINon-inhibitor0.6998
Renal organic cation transporterNon-inhibitor0.859
CYP450 2C9 substrateNon-substrate0.8679
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.7032
CYP450 1A2 substrateInhibitor0.9106
CYP450 2C9 inhibitorNon-inhibitor0.9072
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.8332
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6647
Ames testAMES toxic0.6799
CarcinogenicityNon-carcinogens0.9001
BiodegradationNot ready biodegradable1.0
Rat acute toxicity3.6843 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9775
hERG inhibition (predictor II)Non-inhibitor0.8734
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Sanofi aventis us llc
  • Impax laboratories inc
Packagers
Dosage forms
FormRouteStrength
Tabletoral50 mg
Tabletoral50 mg/1
Tablet, film coatedoral50 mg/1
Prices
Unit descriptionCostUnit
Rilutek 50 mg tablet18.77USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2117466 No2000-01-252012-10-22Canada
CA2151604 No2005-09-202013-12-10Canada
US5527814 No1993-06-182013-06-18Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point119 °CNot Available
logP2.3Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0395 mg/mLALOGPS
logP2.83ALOGPS
logP3.4ChemAxon
logS-3.8ALOGPS
pKa (Strongest Acidic)16.44ChemAxon
pKa (Strongest Basic)4.57ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area48.14 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity44.37 m3·mol-1ChemAxon
Polarizability18.59 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

Pratap Padi, Madhusudhan Ganta, Satyanarayana Bollikonda, Sridhar Chaganti, Ramulu Akula, Loka Maheshwari Dommati, “PROCESS FOR PREPARING RILUZOLE.” U.S. Patent US20080108827, issued May 08, 2008.

US20080108827
General References
  1. Song JH, Huang CS, Nagata K, Yeh JZ, Narahashi T: Differential action of riluzole on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels. J Pharmacol Exp Ther. 1997 Aug;282(2):707-14. [PubMed:9262334 ]
  2. Coric V, Taskiran S, Pittenger C, Wasylink S, Mathalon DH, Valentine G, Saksa J, Wu YT, Gueorguieva R, Sanacora G, Malison RT, Krystal JH: Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. Biol Psychiatry. 2005 Sep 1;58(5):424-8. [PubMed:15993857 ]
  3. van Kan HJ, Groeneveld GJ, Kalmijn S, Spieksma M, van den Berg LH, Guchelaar HJ: Association between CYP1A2 activity and riluzole clearance in patients with amyotrophic lateral sclerosis. Br J Clin Pharmacol. 2005 Mar;59(3):310-3. [PubMed:15752377 ]
  4. Zarate CA Jr, Payne JL, Quiroz J, Sporn J, Denicoff KK, Luckenbaugh D, Charney DS, Manji HK: An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry. 2004 Jan;161(1):171-4. [PubMed:14702270 ]
  5. Mathew SJ, Manji HK, Charney DS: Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology. 2008 Aug;33(9):2080-92. doi: 10.1038/sj.npp.1301652. Epub 2008 Jan 2. [PubMed:18172433 ]
  6. Lamanauskas N, Nistri A: Riluzole blocks persistent Na+ and Ca2+ currents and modulates release of glutamate via presynaptic NMDA receptors on neonatal rat hypoglossal motoneurons in vitro. Eur J Neurosci. 2008 May;27(10):2501-14. doi: 10.1111/j.1460-9568.2008.06211.x. Epub 2008 Apr 26. [PubMed:18445055 ]
External Links
ATC CodesN07XX02
AHFS Codes
  • 28:92.00
PDB EntriesNot Available
FDA labelDownload (125 KB)
MSDSDownload (29.5 KB)
Interactions
Drug Interactions
Drug
CarbamazepineThe metabolism of Riluzole can be increased when combined with Carbamazepine.
Cyproterone acetateThe serum concentration of Riluzole can be decreased when it is combined with Cyproterone acetate.
TeriflunomideThe serum concentration of Riluzole can be decreased when it is combined with Teriflunomide.
Food Interactions
  • Take on an empty stomach 1 hour before or 2 hours after meals.

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Voltage-gated sodium channel activity involved in sa node cell action potential
Specific Function:
This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-resistant Na(+) channel isoform. This channel is respon...
Gene Name:
SCN5A
Uniprot ID:
Q14524
Molecular Weight:
226937.475 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423 ]
  3. Schwartz G, Fehlings MG: Secondary injury mechanisms of spinal cord trauma: a novel therapeutic approach for the management of secondary pathophysiology with the sodium channel blocker riluzole. Prog Brain Res. 2002;137:177-90. [PubMed:12440368 ]
  4. Song JH, Huang CS, Nagata K, Yeh JZ, Narahashi T: Differential action of riluzole on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels. J Pharmacol Exp Ther. 1997 Aug;282(2):707-14. [PubMed:9262334 ]
  5. Weiss S, Benoist D, White E, Teng W, Saint DA: Riluzole protects against cardiac ischaemia and reperfusion damage via block of the persistent sodium current. Br J Pharmacol. 2010 Jul;160(5):1072-82. doi: 10.1111/j.1476-5381.2010.00766.x. [PubMed:20590601 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inducer
General Function:
Cystine:glutamate antiporter activity
Specific Function:
Sodium-independent, high-affinity exchange of anionic amino acids with high specificity for anionic form of cystine and glutamate.
Gene Name:
SLC7A11
Uniprot ID:
Q9UPY5
Molecular Weight:
55422.44 Da
References
  1. Wokke J: Riluzole. Lancet. 1996 Sep 21;348(9030):795-9. [PubMed:8813989 ]
  2. Azbill RD, Mu X, Springer JE: Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes. Brain Res. 2000 Jul 21;871(2):175-80. [PubMed:10899284 ]
  3. Dunlop J, Beal McIlvain H, She Y, Howland DS: Impaired spinal cord glutamate transport capacity and reduced sensitivity to riluzole in a transgenic superoxide dismutase mutant rat model of amyotrophic lateral sclerosis. J Neurosci. 2003 Mar 1;23(5):1688-96. [PubMed:12629173 ]
  4. Gosselin RD, O'Connor RM, Tramullas M, Julio-Pieper M, Dinan TG, Cryan JF: Riluzole normalizes early-life stress-induced visceral hypersensitivity in rats: role of spinal glutamate reuptake mechanisms. Gastroenterology. 2010 Jun;138(7):2418-25. doi: 10.1053/j.gastro.2010.03.003. Epub 2010 Mar 10. [PubMed:20226190 ]
  5. Hayashida K, Parker RA, Eisenach JC: Activation of glutamate transporters in the locus coeruleus paradoxically activates descending inhibition in rats. Brain Res. 2010 Mar 4;1317:80-6. doi: 10.1016/j.brainres.2009.12.086. Epub 2010 Jan 6. [PubMed:20059984 ]

Enzymes

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. 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 ]
  3. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d 24-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.
Gene Name:
CYP1A1
Uniprot ID:
P04798
Molecular Weight:
58164.815 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 ]

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. Milane A, Vautier S, Chacun H, Meininger V, Bensimon G, Farinotti R, Fernandez C: Interactions between riluzole and ABCG2/BCRP transporter. Neurosci Lett. 2009 Mar 6;452(1):12-6. doi: 10.1016/j.neulet.2008.12.061. Epub 2009 Jan 6. [PubMed:19146924 ]
Comments
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Drug created on June 13, 2005 07:24 / Updated on January 27, 2015 16:57