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Identification
NameDantrolene
Accession NumberDB01219  (APRD00901)
TypeSmall Molecule
GroupsApproved
Description

Chemically, dantrolene is a hydantoin derivative, but does not exhibit antiepileptic activity like other hydantoin derivates such as phenytoin.

Structure
Thumb
Synonyms
Dantamacrin
Dantrium
Dantrolene
Dantroleno
Dantrolenum
F-368
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Dantriumcapsule100 mg/1oralPar Pharmaceutical Inc.2008-08-01Not applicableUs
Dantriuminjection20 mg/60mLintravenousPar Pharmaceutical, Inc.2008-08-01Not applicableUs
Dantriumcapsule50 mg/1oralPar Pharmaceutical Inc.2008-08-01Not applicableUs
Dantriumcapsule25 mg/1oralPar Pharmaceutical Inc.2008-08-01Not applicableUs
Dantrium Cap 100mgcapsule100 mgoralNorwich Eaton Canada Inc.1979-12-311996-09-16Canada
Dantrium Cap 25mgcapsule25 mgoralNorwich Eaton Canada Inc.1979-12-311996-09-16Canada
Dantrium Capsulescapsule25 mgoralPar Pharmaceutical Companies1993-12-31Not applicableCanada
Dantrium Capsulescapsule100 mgoralPar Pharmaceutical Companies1993-12-31Not applicableCanada
Dantrium Intravenouspowder for solution20 mgintravenousPar Pharmaceutical Companies1993-12-31Not applicableCanada
Dantrolene Sodiumcapsule100 mg/1oralPar Pharmaceutical Inc.2016-02-19Not applicableUs
Dantrolene Sodiumcapsule50 mg/1oralPar Pharmaceutical Inc.2016-02-19Not applicableUs
Dantrolene Sodiumcapsule50 mg/1oralJHP Pharmaceuticals, LLC2013-04-08Not applicableUs
Dantrolene Sodiumcapsule25 mg/1oralPar Pharmaceutical Inc.2016-02-19Not applicableUs
Dantrolene Sodiumcapsule25 mg/1oralJHP Pharmaceuticals, LLC2013-04-08Not applicableUs
Ryanodex Dantrolene Sodiuminjection, suspension250 mg/5mLintravenousEagle Pharmaceuticals, Inc.2014-07-23Not applicableUs
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Dantrolene Sodiumcapsule25 mg/1oralImpax Generics2005-03-01Not applicableUs
Dantrolene Sodiumcapsule25 mg/1oralCarilion Materials Management2005-03-01Not applicableUs
Dantrolene Sodiumcapsule25 mg/1oralAmerican Health Packaging2008-09-25Not applicableUs
Dantrolene Sodiumcapsule100 mg/1oralImpax Generics2005-03-01Not applicableUs
Dantrolene Sodiumcapsule50 mg/1oralImpax Generics2005-03-01Not applicableUs
Revontoinjection, powder, lyophilized, for solution20 mg/60mLintravenousUs World Meds, Llc2012-06-04Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
DantamacrinSpepharm
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Dantrolene Sodium
Thumb
  • InChI Key: OZOMQRBLCMDCEG-VIZOYTHASA-N
  • Monoisotopic Mass: 314.06511945
  • Average Mass: 314.253
DBSALT000397
Categories
UNIIF64QU97QCR
CAS number7261-97-4
WeightAverage: 314.253
Monoisotopic: 314.06511945
Chemical FormulaC14H10N4O5
InChI KeyInChIKey=OZOMQRBLCMDCEG-VIZOYTHASA-N
InChI
InChI=1S/C14H10N4O5/c19-13-8-17(14(20)16-13)15-7-11-5-6-12(23-11)9-1-3-10(4-2-9)18(21)22/h1-7H,8H2,(H,16,19,20)/b15-7+
IUPAC Name
1-({[5-(4-nitrophenyl)furan-2-yl]methylidene}amino)imidazolidine-2,4-dione
SMILES
[O-][N+](=O)C1=CC=C(C=C1)C1=CC=C(O1)C=NN1CC(=O)NC1=O
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as hydantoins. These are heterocyclic compounds containing an imidazolidine substituted by ketone group at positions 2 and 4.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassAzolidines
Sub ClassImidazolidines
Direct ParentHydantoins
Alternative Parents
Substituents
  • Hydantoin
  • Nitrobenzene
  • Ureide
  • Benzenoid
  • Semicarbazone
  • Monocyclic benzene moiety
  • Heteroaromatic compound
  • Semicarbazide
  • Furan
  • Organic nitro compound
  • Organic nitrite
  • C-nitro compound
  • Carboxamide group
  • Oxacycle
  • Azacycle
  • Organic 1,3-dipolar compound
  • Propargyl-type 1,3-dipolar organic compound
  • Allyl-type 1,3-dipolar organic compound
  • Organic oxoazanium
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organic salt
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Organic zwitterion
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Pharmacology
IndicationFor use, along with appropriate supportive measures, for the management of the fulminant hypermetabolism of skeletal muscle characteristic of malignant hyperthermia crises in patients of all ages. Also used preoperatively, and sometimes postoperatively, to prevent or attenuate the development of clinical and laboratory signs of malignant hyperthermia in individuals judged to be malignant hyperthermia susceptible.
PharmacodynamicsDantrolene is classified as a direct-acting skeletal muscle relaxant. It is currently the only specific and effective treatment for malignant hyperthermia. In isolated nerve-muscle preparation, Dantrium has been shown to produce relaxation by affecting the contractile response of the muscle at a site beyond the myoneural junction. In skeletal muscle, Dantrium dissociates excitation-contraction coupling, probably by interfering with the release of Ca2+ from the sarcoplasmic reticulum. In the anesthetic-induced malignant hyperthermia syndrome, evidence points to an intrinsic abnormality of skeletal muscle tissue. In selected humans, it has been postulated that “triggering agents” (e.g.,general anesthetics and depolarizing neuromuscular blocking agents) produce a change within the cell which results in an elevated myoplasmic calcium. This elevated myoplasmic calcium activates acute cellular catabolic processes that cascade to the malignant hyperthermia crisis. It is hypothesized that addition of Dantrium to the “triggered” malignant hyperthermic muscle cell reestablishes a normal level of ionized calcium in the myoplasm.
Mechanism of actionDantrolene depresses excitation-contraction coupling in skeletal muscle by binding to the ryanodine receptor 1, and decreasing intracellular calcium concentration. Ryanodine receptors mediate the release of calcium from the sarcoplasmic reticulum, an essential step in muscle contraction.
Related Articles
AbsorptionBioavailability is 70%.
Volume of distributionNot Available
Protein bindingSignificant, mostly to albumin.
Metabolism

Hepatic, most likely by hepatic microsomal enzymes. Its major metabolites in body fluids are 5-hydroxydantrolene and an acetylamino metabolite of dantrolene. Another metabolite with an unknown structure appears related to the latter. Dantrium may also undergo hydrolysis and subsequent oxidation forming nitrophenylfuroic acid.

SubstrateEnzymesProduct
Dantrolene
Not Available
5-hydroxydantroleneDetails
Route of eliminationNot Available
Half lifeThe mean biologic half-life after intravenous administration is variable, between 4 to 8 hours under most experimental conditions, while oral is 8.7 hours for a 100mg dose.
ClearanceNot Available
ToxicityOral LD50 in rats is 7400 mg/kg. Symptoms which may occur in case of overdose include, but are not limited to, muscular weakness and alterations in the state of consciousness (e.g., lethargy, coma), vomiting, diarrhea, and crystalluria.
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+0.9974
Blood Brain Barrier+0.9581
Caco-2 permeable-0.5587
P-glycoprotein substrateNon-substrate0.6562
P-glycoprotein inhibitor INon-inhibitor0.8977
P-glycoprotein inhibitor IINon-inhibitor0.978
Renal organic cation transporterNon-inhibitor0.8656
CYP450 2C9 substrateNon-substrate0.81
CYP450 2D6 substrateNon-substrate0.8935
CYP450 3A4 substrateSubstrate0.5848
CYP450 1A2 substrateInhibitor0.8916
CYP450 2C9 inhibitorNon-inhibitor0.8808
CYP450 2D6 inhibitorNon-inhibitor0.9203
CYP450 2C19 inhibitorNon-inhibitor0.8752
CYP450 3A4 inhibitorNon-inhibitor0.8985
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7676
Ames testAMES toxic0.8925
CarcinogenicityNon-carcinogens0.8732
BiodegradationReady biodegradable0.5901
Rat acute toxicity2.5390 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7215
hERG inhibition (predictor II)Non-inhibitor0.9223
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Injectionintravenous20 mg/60mL
Capsuleoral100 mg
Capsuleoral25 mg
Powder for solutionintravenous20 mg
Capsuleoral100 mg/1
Capsuleoral25 mg/1
Capsuleoral50 mg/1
Injection, powder, lyophilized, for solutionintravenous20 mg/60mL
Injection, suspensionintravenous250 mg/5mL
Prices
Unit descriptionCostUnit
Dantrium 20 mg vial106.37USD vial
Dantrolene sodium 20 mg vial97.2USD vial
Dantrolene sodium powder17.6USD g
Dantrium 100 mg capsule2.4USD capsule
Dantrolene sodium 100 mg capsule2.03USD capsule
Dantrium 50 mg capsule1.93USD capsule
Dantrolene sodium 50 mg capsule1.63USD capsule
Dantrium 25 mg capsule1.29USD capsule
Dantrolene sodium 25 mg capsule1.09USD capsule
Dantrium 100 mg Capsule0.8USD capsule
Dantrium 25 mg Capsule0.4USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7758890 No2005-07-012025-07-01Us
US8110225 No2002-12-242022-12-24Us
US8604072 No2002-12-242022-12-24Us
US8685460 No2003-02-152023-02-15Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point279-280 °CDavis, C.S. and Snyder, H.R. Jr.; US. Patent 3,415,821; December 10, 1968; assigned to The Norwich Pharmacal Company.
water solubilityLow (146 mg/L)Not Available
logP1.70JANSEN,ACA ET AL. (1991)
Predicted Properties
PropertyValueSource
Water Solubility0.0805 mg/mLALOGPS
logP1.65ALOGPS
logP1.26ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)9.23ChemAxon
pKa (Strongest Basic)-1.4ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area120.73 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity78.87 m3·mol-1ChemAxon
Polarizability29.98 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Davis, C.S. and Snyder, H.R. Jr.; US. Patent 3,415,821; December 10, 1968; assigned to
The Norwich Pharmacal Company.

General References
  1. Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F: Dantrolene--a review of its pharmacology, therapeutic use and new developments. Anaesthesia. 2004 Apr;59(4):364-73. [PubMed:15023108 ]
External Links
ATC CodesM03CA01
AHFS Codes
  • 12:20.00
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (43 KB)
Interactions
Drug Interactions
Drug
AprepitantThe serum concentration of Dantrolene can be increased when it is combined with Aprepitant.
AzelastineDantrolene may increase the central nervous system depressant (CNS depressant) activities of Azelastine.
BaclofenThe risk or severity of adverse effects can be increased when Baclofen is combined with Dantrolene.
BepridilDantrolene may increase the hyperkalemic activities of Bepridil.
BexaroteneThe serum concentration of Dantrolene can be decreased when it is combined with Bexarotene.
BosentanThe serum concentration of Dantrolene can be decreased when it is combined with Bosentan.
BrimonidineBrimonidine may increase the central nervous system depressant (CNS depressant) activities of Dantrolene.
BuprenorphineDantrolene may increase the central nervous system depressant (CNS depressant) activities of Buprenorphine.
ConivaptanThe serum concentration of Dantrolene can be increased when it is combined with Conivaptan.
DabrafenibThe serum concentration of Dantrolene can be decreased when it is combined with Dabrafenib.
DasatinibThe serum concentration of Dantrolene can be increased when it is combined with Dasatinib.
DeferasiroxThe serum concentration of Dantrolene can be decreased when it is combined with Deferasirox.
DexketoprofenThe risk or severity of adverse effects can be increased when Dexketoprofen is combined with Dantrolene.
DiltiazemDantrolene may increase the hyperkalemic activities of Diltiazem.
DoxylamineDoxylamine may increase the central nervous system depressant (CNS depressant) activities of Dantrolene.
DronabinolDronabinol may increase the central nervous system depressant (CNS depressant) activities of Dantrolene.
DroperidolDroperidol may increase the central nervous system depressant (CNS depressant) activities of Dantrolene.
EthanolDantrolene may increase the central nervous system depressant (CNS depressant) activities of Ethanol.
FluconazoleThe metabolism of Dantrolene can be decreased when combined with Fluconazole.
FosaprepitantThe serum concentration of Dantrolene can be increased when it is combined with Fosaprepitant.
Fusidic AcidThe serum concentration of Dantrolene can be increased when it is combined with Fusidic Acid.
HydrocodoneDantrolene may increase the central nervous system depressant (CNS depressant) activities of Hydrocodone.
HydroxyzineHydroxyzine may increase the central nervous system depressant (CNS depressant) activities of Dantrolene.
IdelalisibThe serum concentration of Dantrolene can be increased when it is combined with Idelalisib.
IvacaftorThe serum concentration of Dantrolene can be increased when it is combined with Ivacaftor.
LacidipineThe risk or severity of adverse effects can be increased when Lacidipine is combined with Dantrolene.
LorazepamThe risk or severity of adverse effects can be increased when Lorazepam is combined with Dantrolene.
LuliconazoleThe serum concentration of Dantrolene can be increased when it is combined with Luliconazole.
Magnesium SulfateMagnesium Sulfate may increase the central nervous system depressant (CNS depressant) activities of Dantrolene.
MethotrimeprazineDantrolene may increase the central nervous system depressant (CNS depressant) activities of Methotrimeprazine.
MetyrosineDantrolene may increase the sedative activities of Metyrosine.
MifepristoneThe serum concentration of Dantrolene can be increased when it is combined with Mifepristone.
MinocyclineMinocycline may increase the central nervous system depressant (CNS depressant) activities of Dantrolene.
MirtazapineDantrolene may increase the central nervous system depressant (CNS depressant) activities of Mirtazapine.
MitotaneThe serum concentration of Dantrolene can be decreased when it is combined with Mitotane.
NabiloneNabilone may increase the central nervous system depressant (CNS depressant) activities of Dantrolene.
NelfinavirThe metabolism of Dantrolene can be decreased when combined with Nelfinavir.
NetupitantThe serum concentration of Dantrolene can be increased when it is combined with Netupitant.
OrphenadrineDantrolene may increase the central nervous system depressant (CNS depressant) activities of Orphenadrine.
PalbociclibThe serum concentration of Dantrolene can be increased when it is combined with Palbociclib.
ParaldehydeDantrolene may increase the central nervous system depressant (CNS depressant) activities of Paraldehyde.
ParoxetineThe risk or severity of adverse effects can be increased when Dantrolene is combined with Paroxetine.
PerampanelPerampanel may increase the central nervous system depressant (CNS depressant) activities of Dantrolene.
PhenytoinThe metabolism of Dantrolene can be increased when combined with Phenytoin.
PramipexoleDantrolene may increase the sedative activities of Pramipexole.
RopiniroleDantrolene may increase the sedative activities of Ropinirole.
RotigotineDantrolene may increase the sedative activities of Rotigotine.
RufinamideThe risk or severity of adverse effects can be increased when Rufinamide is combined with Dantrolene.
SiltuximabThe serum concentration of Dantrolene can be decreased when it is combined with Siltuximab.
SimeprevirThe serum concentration of Dantrolene can be increased when it is combined with Simeprevir.
Sodium oxybateSodium oxybate may increase the central nervous system depressant (CNS depressant) activities of Dantrolene.
St. John's WortThe serum concentration of Dantrolene can be decreased when it is combined with St. John's Wort.
StiripentolThe serum concentration of Dantrolene can be increased when it is combined with Stiripentol.
SuvorexantDantrolene may increase the central nervous system depressant (CNS depressant) activities of Suvorexant.
TapentadolTapentadol may increase the central nervous system depressant (CNS depressant) activities of Dantrolene.
ThalidomideDantrolene may increase the central nervous system depressant (CNS depressant) activities of Thalidomide.
TocilizumabThe serum concentration of Dantrolene can be decreased when it is combined with Tocilizumab.
VecuroniumDantrolene may increase the neuromuscular blocking activities of Vecuronium.
VerapamilDantrolene may increase the hyperkalemic activities of Verapamil.
ZolpidemDantrolene may increase the central nervous system depressant (CNS depressant) activities of Zolpidem.
Food Interactions
  • Take without regard to meals.

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Voltage-gated calcium channel activity
Specific Function:
Calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm and thereby plays a key role in triggering muscle contraction following depolarization of T-tubules. Repeated very high-level exercise increases the open probability of the channel and leads to Ca(2+) leaking into the cytoplasm. Can also mediate the release of Ca(2+) from intracellular stores ...
Gene Name:
RYR1
Uniprot ID:
P21817
Molecular Weight:
565170.715 Da
References
  1. Britt BA, Scott E, Frodis W, Clements MJ, Endrenyi L: Dantrolene--in vitro studies in malignant hyperthermia susceptible (MHS) and normal skeletal muscle. Can Anaesth Soc J. 1984 Mar;31(2):130-54. [PubMed:6704779 ]
  2. Harrison GG: Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium. 1975. Br J Anaesth. 1998 Oct;81(4):626-9; discussion 625. [PubMed:9924249 ]
  3. Flewellen EH, Nelson TE: Dantrolene dose response in malignant hyperthermia-susceptible (MHS) swine: method to obtain prophylaxis and therapeusis. Anesthesiology. 1980 Apr;52(4):303-8. [PubMed:7362049 ]
  4. Tonner PH, Scholz J, Richter A, Loscher W, Steinfath M, Wappler F, Wlaz P, Hadji B, Roewer N, Schulte am Esch J: Alterations of inositol polyphosphates in skeletal muscle during porcine malignant hyperthermia. Br J Anaesth. 1995 Oct;75(4):467-71. [PubMed:7488490 ]
  5. Zhao X, Weisleder N, Han X, Pan Z, Parness J, Brotto M, Ma J: Azumolene inhibits a component of store-operated calcium entry coupled to the skeletal muscle ryanodine receptor. J Biol Chem. 2006 Nov 3;281(44):33477-86. Epub 2006 Aug 31. [PubMed:16945924 ]
  6. Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F: Dantrolene--a review of its pharmacology, therapeutic use and new developments. Anaesthesia. 2004 Apr;59(4):364-73. [PubMed:15023108 ]
  7. Gerbershagen MU, Fiege M, Krause T, Agarwal K, Wappler F: [Dantrolene. Pharmacological and therapeutic aspects]. Anaesthesist. 2003 Mar;52(3):238-45. [PubMed:12666006 ]
  8. Paul-Pletzer K, Yamamoto T, Bhat MB, Ma J, Ikemoto N, Jimenez LS, Morimoto H, Williams PG, Parness J: Identification of a dantrolene-binding sequence on the skeletal muscle ryanodine receptor. J Biol Chem. 2002 Sep 20;277(38):34918-23. Epub 2002 Jul 11. [PubMed:12167662 ]
  9. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d3 25-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 performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 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 ]
Comments
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Drug created on June 13, 2005 07:24 / Updated on August 24, 2016 01:53