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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
SynonymLanguageCode
DantrolenoSpanishINN
DantrolenumLatinINN
Salts
Name/CAS Structure Properties
Dantrolene Sodium
Thumb
  • InChI Key: OZOMQRBLCMDCEG-VIZOYTHASA-N
  • Monoisotopic Mass: 314.06511945
  • Average Mass: 314.253
DBSALT000397
Brand names
NameCompany
DantriumNot Available
Dantrium IntravenousNot Available
Brand mixturesNot Available
Categories
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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassAzolidines
SubclassImidazolidines
Direct parentHydantoins
Alternative parentsNitrobenzenes; Ureides; Semicarbazones; Hydrazones; Furans; N-unsubstituted Carboxylic Acid Imides; Nitronic Acids; Aldimines; Secondary Carboxylic Acid Amides; Nitro Compounds; Organic Oxoazanium Compounds; Polyamines; Carboxylic Acids
Substituentsnitrobenzene; ureide; semicarbazone; benzene; furan; semicarbazide; hydrazone; carboxylic acid imide, n-unsubstituted; carboxamide group; nitro compound; aldimine; nitronic acid; secondary carboxylic acid amide; organic oxoazanium; carboxylic acid; polyamine; carboxylic acid derivative; imine; organonitrogen compound; amine
Classification descriptionThis compound belongs to the hydantoins. These are heterocyclic compounds containing an imidazolidine substituted by ketone group at positions 2 and 4.
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.
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
    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
    Property Value Probability
    Human Intestinal Absorption + 0.9974
    Blood Brain Barrier + 0.9581
    Caco-2 permeable - 0.5587
    P-glycoprotein substrate Non-substrate 0.6562
    P-glycoprotein inhibitor I Non-inhibitor 0.8977
    P-glycoprotein inhibitor II Non-inhibitor 0.978
    Renal organic cation transporter Non-inhibitor 0.8656
    CYP450 2C9 substrate Non-substrate 0.81
    CYP450 2D6 substrate Non-substrate 0.8935
    CYP450 3A4 substrate Substrate 0.5848
    CYP450 1A2 substrate Inhibitor 0.8916
    CYP450 2C9 substrate Non-inhibitor 0.8808
    CYP450 2D6 substrate Non-inhibitor 0.9203
    CYP450 2C19 substrate Non-inhibitor 0.8752
    CYP450 3A4 substrate Non-inhibitor 0.8985
    CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.7676
    Ames test AMES toxic 0.8925
    Carcinogenicity Non-carcinogens 0.8732
    Biodegradation Ready biodegradable 0.5901
    Rat acute toxicity 2.5390 LD50, mol/kg Not applicable
    hERG inhibition (predictor I) Weak inhibitor 0.7215
    hERG inhibition (predictor II) Non-inhibitor 0.9223
    Pharmacoeconomics
    Manufacturers
    • Jhp pharmaceuticals llc
    • Actavis totowa llc
    • Impax laboratories inc
    • Us worldmeds llc
    Packagers
    Dosage forms
    FormRouteStrength
    CapsuleOral
    Powder, for solutionIntravenous
    Prices
    Unit descriptionCostUnit
    Dantrium 20 mg vial106.37USDvial
    Dantrolene sodium 20 mg vial97.2USDvial
    Dantrolene sodium powder17.6USDg
    Dantrium 100 mg capsule2.4USDcapsule
    Dantrolene sodium 100 mg capsule2.03USDcapsule
    Dantrium 50 mg capsule1.93USDcapsule
    Dantrolene sodium 50 mg capsule1.63USDcapsule
    Dantrium 25 mg capsule1.29USDcapsule
    Dantrolene sodium 25 mg capsule1.09USDcapsule
    Dantrium 100 mg Capsule0.8USDcapsule
    Dantrium 25 mg Capsule0.4USDcapsule
    DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
    PatentsNot Available
    Properties
    Statesolid
    Experimental Properties
    PropertyValueSource
    melting point279-280 °CPhysProp
    water solubilityLow (146 mg/L)Not Available
    logP1.70JANSEN,ACA ET AL. (1991)
    Predicted Properties
    PropertyValueSource
    water solubility8.05e-02 g/lALOGPS
    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 area120.73ChemAxon
    rotatable bond count4ChemAxon
    refractivity78.87ChemAxon
    polarizability29.98ChemAxon
    number of rings3ChemAxon
    bioavailability1ChemAxon
    rule of fiveYesChemAxon
    Ghose filterYesChemAxon
    Veber's ruleNoChemAxon
    MDDR-like ruleNoChemAxon
    Spectra
    SpectraNot Available
    References
    Synthesis ReferenceNot Available
    General Reference
    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
    External Links
    ResourceLink
    KEGG DrugD02347
    KEGG CompoundC06939
    ChEBI4317
    ChEMBLCHEMBL1201288
    Therapeutic Targets DatabaseDNC001623
    PharmGKBPA449208
    IUPHAR4172
    Guide to Pharmacology4172
    Drug Product Database1997602
    RxListhttp://www.rxlist.com/cgi/generic/dantrolene.htm
    Drugs.comhttp://www.drugs.com/cdi/dantrolene.html
    WikipediaDantrolene
    ATC CodesM03CA01
    AHFS Codes
    • 12:20.00
    PDB EntriesNot Available
    FDA labelNot Available
    MSDSshow(43 KB)
    Interactions
    Drug Interactions
    Drug
    AtazanavirAtazanavir may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if atazanavir is initiated, discontinued or dose changed.
    ClarithromycinClarithromycin may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if clarithromycin is initiated, discontinued or dose changed.
    ConivaptanConivaptan may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if conivaptan is initiated, discontinued or dose changed.
    DarunavirDarunavir may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if darunavir is initiated, discontinued or dose changed.
    DelavirdineDelavirdine may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if delavirdine is initiated, discontinued or dose changed.
    FosamprenavirFosamprenavir may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if fosamprenavir is initiated, discontinued or dose changed.
    ImatinibImatinib may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if imatinib is initiated, discontinued or dose changed.
    IndinavirIndinavir may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if indinavir is initiated, discontinued or dose changed.
    IsoniazidIsoniazid may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if isoniazid is initiated, discontinued or dose changed.
    ItraconazoleItraconazole may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if itraconazole is initiated, discontinued or dose changed.
    KetoconazoleKetoconazole may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if ketoconazole is initiated, discontinued or dose changed.
    LopinavirLopinavir may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if lopinavir is initiated, discontinued or dose changed.
    MethotrimeprazineConcomitant therapy may result in additive CNS depressant effects. The dosage of dantrolene should be decreased by 50% prior to initiating concomitant therapy. Monitor for increased CNS depression.
    NefazodoneNefazodone may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if nefazodone is initiated, discontinued or dose changed.
    NelfinavirNelfinavir may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if nelfinavir is initiated, discontinued or dose changed.
    NicardipineNicardipine may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if nicardipine is initiated, discontinued or dose changed.
    PosaconazolePosaconazole may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if posaconazole is initiated, discontinued or dose changed.
    QuinidineQuinidine may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if quinidine is initiated, discontinued or dose changed.
    RitonavirRitonavir may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if ritonavir is initiated, discontinued or dose changed.
    SaquinavirSaquinavir may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if saquinavir is initiated, discontinued or dose changed.
    TelithromycinTelithromycin may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if telithromycin is initiated, discontinued or dose changed.
    TriprolidineThe CNS depressants, Triprolidine and Dantrolene, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
    VoriconazoleVoriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if voriconazole is initiated, discontinued or dose changed.
    Food Interactions
    • Take without regard to meals.

    1. Ryanodine receptor 1

    Kind: protein

    Organism: Human

    Pharmacological action: yes

    Actions: antagonist

    Components

    Name UniProt ID Details
    Ryanodine receptor 1 P21817 Details

    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
    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
    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
    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
    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
    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
    7. Gerbershagen MU, Fiege M, Krause T, Agarwal K, Wappler F: [Dantrolene. Pharmacological and therapeutic aspects] Anaesthesist. 2003 Mar;52(3):238-45. Pubmed
    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
    9. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

    1. Cytochrome P450 3A4

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Cytochrome P450 3A4 P08684 Details

    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. Epub 2009 Nov 24. Pubmed

    Comments
    Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13