Identification

Name
Dantrolene
Accession Number
DB01219  (APRD00901)
Type
Small Molecule
Groups
Approved, Investigational
Description

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

Structure
Thumb
Synonyms
  • Dantamacrin
  • Dantrolene
  • Dantroleno
  • Dantrolenum
  • F-368
Product Ingredients
IngredientUNIICASInChI Key
Dantrolene Sodium287M0347EV24868-20-0KSRLIXGNPXAZHD-UHFFFAOYSA-M
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DantriumCapsule100 mg/1OralPar Pharmaceutical2008-08-012015-07-31Us
DantriumCapsule25 mg/1OralPar Pharmaceutical2008-08-01Not applicableUs
DantriumInjection20 mg/60mLIntravenousProcter and Gamble Pharmaceuticals2006-02-06Not applicableUs
DantriumCapsule25 mg/1OralProcter & Gamble Pharmaceuticals2006-03-28Not applicableUs
DantriumCapsule100 mg/1OralProcter & Gamble Pharmaceuticals2006-03-28Not applicableUs
DantriumCapsule50 mg/1OralPar Pharmaceutical2008-08-01Not applicableUs
DantriumInjection20 mg/60mLIntravenousPar Pharmaceutical2009-04-20Not applicableUs
DantriumCapsule50 mg/1OralProcter & Gamble Pharmaceuticals2006-03-28Not 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
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DantroleneInjection, powder, for solution20 mg/1IntravenousWest-Ward Pharmaceuticals Corp2017-06-19Not applicableUs
Dantrolene SodiumCapsule25 mg/1OralPar Pharmaceutical2016-03-28Not applicableUs
Dantrolene SodiumCapsule100 mg/1OralImpax Generics2005-03-01Not applicableUs0115 443320180913 8702 19acmak
Dantrolene SodiumCapsule25 mg/1OralImpax Generics2005-03-01Not applicableUs
Dantrolene SodiumCapsule25 mg/1OralPar Pharmaceutical2013-04-082020-05-31Us
Dantrolene SodiumCapsule100 mg/1OralPar Pharmaceutical2016-03-28Not applicableUs
Dantrolene SodiumCapsule25 mg/1OralAmerincan Health Packaging2008-09-29Not applicableUs
Dantrolene SodiumCapsule25 mg/1OralCardinal Health2008-09-25Not applicableUs
Dantrolene SodiumCapsule25 mg/1OralCarilion Materials Management2005-03-01Not applicableUs
Dantrolene SodiumCapsule50 mg/1OralPar Pharmaceutical2016-03-28Not applicableUs
International/Other Brands
Dantamacrin (Spepharm) / Dantrium
Categories
UNII
F64QU97QCR
CAS number
7261-97-4
Weight
Average: 314.253
Monoisotopic: 314.06511945
Chemical Formula
C14H10N4O5
InChI Key
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

Pharmacology

Indication

For 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.

Associated Conditions
Pharmacodynamics

Dantrolene 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 action

Dantrolene 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.

TargetActionsOrganism
ARyanodine receptor 1
antagonist
Human
Absorption

Bioavailability is 70%.

Volume of distribution
Not Available
Protein binding

Significant, 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.

Route of elimination
Not Available
Half life

The 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.

Clearance
Not Available
Toxicity

Oral 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
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Dantrolene.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Dantrolene.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Dantrolene is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when Dantrolene is combined with 3,4-Methylenedioxyamphetamine.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Dantrolene.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when Dantrolene is combined with 4-Bromo-2,5-dimethoxyamphetamine.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Dantrolene.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when Dantrolene is combined with 4-Methoxyamphetamine.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Dantrolene.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when Dantrolene is combined with 5-methoxy-N,N-dimethyltryptamine.
Food Interactions
  • Take without regard to meals.

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
KEGG Drug
D02347
KEGG Compound
C06939
PubChem Compound
6914273
PubChem Substance
46504976
ChemSpider
5290202
BindingDB
50198767
ChEBI
4317
ChEMBL
CHEMBL1201288
Therapeutic Targets Database
DNC001623
PharmGKB
PA449208
IUPHAR
4172
Guide to Pharmacology
GtP Drug Page
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Dantrolene
ATC Codes
M03CA01 — Dantrolene
AHFS Codes
  • 12:20.08 — Direct-acting Skeletal Muscle Relaxants
MSDS
Download (43 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2CompletedTreatmentCerebral Vasospasm After Subarachnoid Hemorrhage1
1, 2CompletedTreatmentCerebral Vasospasm / Subarachnoid Hemorrhage1
1, 2RecruitingTreatmentAtaxia / Diabetes Mellitus (DM) / Optic Nerve Atrophy / Wolfram Syndrome1
2, 3TerminatedTreatmentHyperthermia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Amerisource Health Services Corp.
  • DSM Corp.
  • Global Pharmaceuticals
  • JHP Pharmaceuticals LLC
  • Kaiser Foundation Hospital
  • Medisca Inc.
  • Murfreesboro Pharmaceutical Nursing Supply
  • Norwich Pharmaceuticals Inc.
  • Southwood Pharmaceuticals
  • US WorldMeds
  • Warner Chilcott Co. Inc.
Dosage forms
FormRouteStrength
CapsuleOral100 mg/1
CapsuleOral25 mg/1
CapsuleOral50 mg/1
InjectionIntravenous20 mg/60mL
CapsuleOral100 mg
CapsuleOral25 mg
Powder, for solutionIntravenous20 mg
Injection, powder, for solutionIntravenous20 mg/1
Injection, solutionIntravenous20 mg/60mL
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)
US8685460No2014-04-012023-02-15Us
US7758890No2010-07-202025-07-01Us
US8110225No2012-02-072022-12-24Us
US8604072No2013-12-102022-12-24Us
US9884044No2018-02-062022-06-13Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)279-280 °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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Azolidines
Sub Class
Imidazolidines
Direct Parent
Hydantoins
Alternative Parents
Alpha amino acids and derivatives / Nitrobenzenes / Nitroaromatic compounds / Semicarbazones / Dicarboximides / Furans / Heteroaromatic compounds / Organic carbonic acids and derivatives / Oxacyclic compounds / Azacyclic compounds
show 7 more
Substituents
Hydantoin / Alpha-amino acid or derivatives / Nitrobenzene / Nitroaromatic compound / Monocyclic benzene moiety / Semicarbazone / Benzenoid / Heteroaromatic compound / Dicarboximide / Furan
show 21 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
hydrazone, imidazolidine-2,4-dione (CHEBI:4317)

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-tu...
Gene Name
RYR1
Uniprot ID
P21817
Uniprot Name
Ryanodine receptor 1
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
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]

Drug created on June 13, 2005 07:24 / Updated on November 18, 2018 13:31