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Identification
Name Dantrolene
Accession Number DB01219 (APRD00901)
Type small molecule
Groups approved
Description

Chemically, dantrolene is a hydantoin derivative, but does not exhibit antiepileptic activity like other hydantoin derivates such as phenytoin.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Dantrolene Sodium
Dantroleno [INN-Spanish]
Dantrolenum [INN-Latin]
Salts Not Available
Brand names
Name Company
Dantrium
Dantrium Intravenous
Brand mixtures Not Available
Categories
  • Muscle Relaxants, Central
CAS number 7261-97-4
Weight Average: 314.253
Monoisotopic: 314.06511945
Chemical Formula C14H10N4O5
InChI Key InChIKey=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+
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Not Available
Classes Not Available
Substructures Not Available
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.
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.
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
Pharmacoeconomics
Manufacturers
  • Jhp pharmaceuticals llc
  • Actavis totowa llc
  • Impax laboratories inc
  • Us worldmeds llc
Packagers
Dosage forms
Form Route Strength
Capsule Oral
Powder, for solution Intravenous
Prices
Unit description Cost Unit
Dantrium 20 mg vial 106.37 USD vial
Dantrolene sodium 20 mg vial 97.2 USD vial
Dantrolene sodium powder 17.6 USD g
Dantrium 100 mg capsule 2.4 USD capsule
Dantrolene sodium 100 mg capsule 2.03 USD capsule
Dantrium 50 mg capsule 1.93 USD capsule
Dantrolene sodium 50 mg capsule 1.63 USD capsule
Dantrium 25 mg capsule 1.29 USD capsule
Dantrolene sodium 25 mg capsule 1.09 USD capsule
Dantrium 100 mg Capsule 0.8 USD capsule
Dantrium 25 mg Capsule 0.4 USD capsule
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Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 279-280 °C PhysProp
water solubility Low (146 mg/L) Not Available
logP 1.70 JANSEN,ACA ET AL. (1991)
Predicted Properties
Property Value Source
water solubility 8.05e-02 g/l ALOGPS
logP 1.65 ALOGPS
logP 1.26 ChemAxon
logS -3.6 ALOGPS
pKa (strongest acidic) 9.23 ChemAxon
pKa (strongest basic) -1.4 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 5 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 120.73 ChemAxon
rotatable bond count 4 ChemAxon
refractivity 78.87 ChemAxon
polarizability 29.98 ChemAxon
References
Synthesis Reference Not 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
Resource Link
KEGG Drug D02347 Link_out
KEGG Compound C06939 Link_out
ChEBI 4317 Link_out
ChEMBL 4317 Link_out
Therapeutic Targets Database DNC001623 Link_out
PharmGKB PA449208 Link_out
IUPHAR 4172 Link_out
Guide to Pharmacology 4172 Link_out
Drug Product Database 1997602 Link_out
RxList http://www.rxlist.com/cgi/generic/dantrolene.htm Link_out
Drugs.com http://www.drugs.com/cdi/dantrolene.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Dantrolene Link_out
ATC Codes
  • M03CA01
AHFS Codes
  • 12:20.00
PDB Entries Not Available
FDA label Not Available
MSDS show (43 KB)
Interactions
Drug Interactions
Drug Interaction
Atazanavir Atazanavir 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.
Clarithromycin Clarithromycin 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.
Conivaptan Conivaptan 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.
Darunavir Darunavir 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.
Delavirdine Delavirdine 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.
Fosamprenavir Fosamprenavir 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.
Imatinib Imatinib 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.
Indinavir Indinavir 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.
Isoniazid Isoniazid 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.
Itraconazole Itraconazole 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.
Ketoconazole Ketoconazole 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.
Lopinavir Lopinavir 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.
Methotrimeprazine Concomitant 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.
Nefazodone Nefazodone 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.
Nelfinavir Nelfinavir 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.
Nicardipine Nicardipine 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.
Posaconazole Posaconazole 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.
Quinidine Quinidine 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.
Ritonavir Ritonavir 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.
Saquinavir Saquinavir 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.
Telithromycin Telithromycin 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.
Triprolidine The CNS depressants, Triprolidine and Dantrolene, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
Voriconazole Voriconazole, 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.
Targets

1. Ryanodine receptor 1

Pharmacological action: yes
Actions: antagonist

Communication between transverse-tubules and sarcoplasmic reticulum. Contraction of skeletal muscle is triggered by release of calcium ions from SR following depolarization of T-tubules

Organism class: human
UniProt ID: P21817 Link_out
Gene: RYR1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Enzymes

1. Cytochrome P450 3A4

Actions: substrate

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 xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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 February 08, 2013 16:20