DANTROLENE SODIUM

Details

Stereochemistry	ACHIRAL
Molecular Formula	2C14H9N4O5.2Na.7H2O
Molecular Weight	798.5766
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	2
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

O.O.O.O.O.O.O.[Na+].[Na+].[O-][N+](=O)C1=CC=C(C=C1)C2=CC=C(O2)\C=N\N3CC(=O)[N-]C3=O.[O-][N+](=O)C4=CC=C(C=C4)C5=CC=C(O5)\C=N\N6CC(=O)[N-]C6=O

InChI

InChIKey=LTWQNYPDAUSXBC-CDJGKPBYSA-L

InChI=1S/2C14H10N4O5.2Na.7H2O/c2*19-13-8-17(14(20)16-13)15-7-11-5-6-12(23-11)9-1-3-10(4-2-9)18(21)22;;;;;;;;;/h2*1-7H,8H2,(H,16,19,20);;;7*1H2/q;;2*+1;;;;;;;/p-2/b2*15-7+;;;;;;;;;

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/15023108
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/9341133, http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf

Dantrolene is a drug which was approved by FDA for the treatment of chronic spasticity and malignant hyperthermia (a rare life-threatening clinical syndrome). Dantrolene effect was shown both in vivo and in vitro and proved to be mediated by interaction with Ryanodine receptor 1. The drug has a potential for hepatotoxicity and should be used as indicated in the label.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Ryanodine receptor 1 4 Target ID: P21817 Gene ID: 6261.0 Gene Symbol: RYR1 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/15023108	Antagonist 2778		130.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Chronic spasticity 3 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf	Primary		Approved 8429	DANTRIUM Approved Use In Chronic Spasticity: Dantrium is indicated in controlling the manifestations of clinical spasticity resulting from upper motor neuron disorders (e.g., spinal cord injury, stroke, cerebral palsy, or multiple sclerosis). In Malignant Hyperthermia: Oral Dantrium is also indicated preoperatively to prevent or attenuate the development of signs of malignant hyperthermia in known, or strongly suspect, malignant hyperthermia susceptible patients who require anesthesia and/or surgery. Launch Date 1974
Malignant hyperthermia 3 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf	Preventing		Approved 8429	DANTRIUM Approved Use In Chronic Spasticity: Dantrium is indicated in controlling the manifestations of clinical spasticity resulting from upper motor neuron disorders (e.g., spinal cord injury, stroke, cerebral palsy, or multiple sclerosis). In Malignant Hyperthermia: Oral Dantrium is also indicated preoperatively to prevent or attenuate the development of signs of malignant hyperthermia in known, or strongly suspect, malignant hyperthermia susceptible patients who require anesthesia and/or surgery. Launch Date 1974

C_max

Value	Dose	Co-administered	Analyte	Population
9 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205579s000lbl.pdf	2.5 mg/kg single, intravenous dose: 2.5 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		DANTROLENE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
77.7 μg × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205579s000lbl.pdf	2.5 mg/kg single, intravenous dose: 2.5 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		DANTROLENE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
8.7 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf	100 mg 1 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered:		DANTROLENE blood	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
10.8 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205579s000lbl.pdf	2.5 mg/kg single, intravenous dose: 2.5 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		DANTROLENE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
25 mg 1 times / day steady, oral (starting) Dose: 25 mg, 1 times / day Route: oral Route: steady Dose: 25 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf	Disc. AE: Hepatitis, Diarrhea... AEs leading to discontinuation/dose reduction: Hepatitis Diarrhea Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf

AEs

AE	Significance	Dose	Population
Diarrhea	Disc. AE	25 mg 1 times / day steady, oral (starting) Dose: 25 mg, 1 times / day Route: oral Route: steady Dose: 25 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf
Hepatitis	Disc. AE	25 mg 1 times / day steady, oral (starting) Dose: 25 mg, 1 times / day Route: oral Route: steady Dose: 25 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OAT1 599 OAT3 642 MRP4 204	CYP1A1 349 CYP1A2 1054 CYP3A 191 BCRP 561

Drug as perpetrator

Target	Modality	Activity
OAT3 644	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28630284/	yes [IC50 0.3 uM]
OAT1 603	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28630284/	yes [IC50 1.89 uM]
MRP4 238	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28630284/	yes [IC50 5.29 uM]

Drug as victim

Target	Modality	Activity
BCRP 561	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/22115838/	yes
CYP1A1 349	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/7902259/	yes
CYP1A2 1054	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/7902259/	yes
CYP3A 191	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/7902259/	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:4317	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:4317
MolPort	MolPort-003-846-133	https://www.molport.com/shop/molecule-link/MolPort-003-846-133
ZINC	ZINC000252679615	http://zinc15.docking.org/substances/ZINC000252679615

PubMed

Title	Date	PubMed
Treatment of spastic cerebral-palsied children with sodium dantrolene.	1975 Dec	1107103
Letter: Hallucinations associated with dantrolene sodium therapy.	1975 Jan 25	1111870
Dantrolene and suxamethonium. The effect of pre-operative dantrolene on the action of suxamethonium.	1979 Feb	375768
Pneumonitis, pleural effusion and pericarditis following treatment with dantrolene.	1984 May	6736987
Hyperkalemia and cardiovascular collapse after verapamil and dantrolene administration in swine.	1984 May	6711841
Trimipramine-induced neuroleptic malignant syndrome after transient psychogenic polydipsia in one patient.	1989 Apr	2925603
Treatment of lethal catatonia with electroconvulsive therapy and dantrolene sodium: a case report.	1990 Jul	2399829
[Successful treatment of levodopa-induced neuroleptic malignant syndrome (NMS) with disseminated intravascular coagulation (DIC) in a patient with Parkinson's disease].	1991 Jan	2044308
Dantrolene treatment of opioid-induced myoclonus.	1995 Dec	7486124
Clinical effects of intravenously administered dantrolene.	1995 Mar	7861811
[A case of malignant syndrome triggered by the use of haloperidol and chrorpromazine].	1997 Apr	9128030
Malignant hyperthermia induced by general anesthesia for bone marrow harvesting.	1997 Mar	9052921
Dantrolene inhibition of ryanodine receptor Ca2+ release channels. Molecular mechanism and isoform selectivity.	2001 Apr 27	11278295
Mechanism of the beneficial effects of dantrolene sodium on ethanol-induced acute gastric mucosal injury in rats.	2002 May	12123631
Dantrolene--a review of its pharmacology, therapeutic use and new developments.	2004 Apr	15023108
Drug-induced liver injury.	2004 Mar 1	14986274
Carbamazepine toxicity following Oxybutynin and Dantrolene administration: a case report.	2005 Apr	15685264
Prediction of genotoxicity of chemical compounds by statistical learning methods.	2005 Jun	15962942
Prevention of succinylcholine-induced fasciculation and myalgia: a meta-analysis of randomized trials.	2005 Oct	16192781
Postoperative hyperthermia of unknown origin treated with dantrolene sodium.	2005 Spring	15859445
Neuroleptic malignant syndrome with delayed onset of fever following risperidone administration.	2006 Dec	17119106
Secretion of brain-derived neurotrophic factor from brain microvascular endothelial cells.	2006 Mar	16553631
Insulin-like growth factors (IGF) I and II utilize different calcium signaling pathways in a primary human parathyroid cell culture model.	2006 Mar	16485066
KATP channel knockout worsens myocardial calcium stress load in vivo and impairs recovery in stunned heart.	2007 Apr	17189350
Transitional cell carcinoma in the paediatric population: be aware of unusual aetiologies.	2007 Nov	17924939
A novel compound heterozygous dysferlin mutation in Miyoshi myopathy siblings responding to dantrolene.	2007 Nov	17868276
Identification of functional type 1 ryanodine receptors in human dendritic cells.	2007 Oct 19	17707769
Quantitative investigation of the role of breast cancer resistance protein (Bcrp/Abcg2) in limiting brain and testis penetration of xenobiotic compounds.	2008 Jun	18322075
Cellular imaging predictions of clinical drug-induced liver injury.	2008 Sep	18524759
Stimulation of cytosolic and mitochondrial calcium mobilization by indomethacin in Caco-2 cells: modulation by the polyphenols quercetin, resveratrol and rutin.	2012 Dec	23022152
Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model.	2013 Dec	24052561
The calcium signaling pathway regulates leydig cell steroidogenesis through a transcriptional cascade involving the nuclear receptor NR4A1 and the steroidogenic acute regulatory protein.	2013 Jan	23183170
Antispasmodic effect of shakuyakukanzoto extract on experimental muscle cramps in vivo: role of the active constituents of Glycyrrhizae radix.	2013 Jan 9	23164761
Tributyltin-induced endoplasmic reticulum stress and its Ca(2+)-mediated mechanism.	2013 Oct 1	23743301
Genomic models of short-term exposure accurately predict long-term chemical carcinogenicity and identify putative mechanisms of action.	2014	25058030

Patents

Sample Use Guides

In Vivo Use Guide

For Use in Chronic Spasticity: 25 mg once daily for seven days, then 25 mg t.i.d. for seven days, 50 mg t.i.d. for seven days, 100 mg t.i.d. (adults). For Malignant Hyperthermia: administer 4 to 8 mg/kg/day of oral drug in 3 or 4 divided doses for one or two days prior to surgery, with the last dose being given approximately 3 to 4 hours before scheduled surgery with a minimum of water.

Route of Administration: Oral

In Vitro Use Guide

Whole skeletal muscle fascicles were incubated with dantrolene at concentrations of 5, 15 and 25 uM. Dantrolene inhibited twitch tensions of skeletal muscle fascicles, probably by indirectly preventing the release of calcium from the SR.

Name

Type

Language

DANTROLENE SODIUM

Official Name

English

DANTAMACRIN

Brand Name

English

NSC-758403

Code

English

Dantrolene sodium hemiheptahydrate [WHO-DD]

Common Name

English

F-440

Code

English

DANTRIUM

Brand Name

English

DANTROLENE SODIUM HEMIHEPTAHYDRATE

Common Name

English

DANTROLENE SODIUM HYDRATE

Common Name

English

Dantrolene sodium [WHO-DD]

Common Name

English

DANTROLENE SODIUM HEPTAHYDRATE

Common Name

English

DANTROLEN

Brand Name

English

2,4-IMIDAZOLIDINEDIONE, 1-(((5-(4-NITROPHENYL)-2-FURANYL)METHYLENE)AMINO)-, SODIUM SALT, HYDRATE (2:7)

Common Name

English

DANTROLENE SODIUM SALT HEMIHEPTAHYDRATE

Common Name

English

DANTROLENE SODIUM [MART.]

Common Name

English

DANTROLENE SODIUM [ORANGE BOOK]

Common Name

English

DANTROLENE SODIUM [USAN]

Common Name

English

DANTROLENE SODIUM HYDRATE [JAN]

Common Name

English

DANTROLENE SODIUM [USP-RS]

Common Name

English

1-((5-(P-NITROPHENYL)FURFURYLIDENE)AMINO)HYDANTOIN SODIUM SALT HYDRATE

Common Name

English

DANTROLENE SODIUM [VANDF]

Common Name

English

DANTROLENE SODIUM [USP MONOGRAPH]

Common Name

English

DANTROLENE SODIUM SALT HEMIHEPTAHYDRATE [MI]

Common Name

English

RYANODEX

Brand Name

English

Classification Tree Code System Code

EU-Orphan Drug

EU/3/16/1800