DANTROLENE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C14H10N4O5
Molecular Weight	314.253
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[O-][N+](=O)C1=CC=C(C=C1)C2=CC=C(O2)\C=N\N3CC(=O)NC3=O

InChI

InChIKey=OZOMQRBLCMDCEG-VIZOYTHASA-N

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+

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 hepatitis.	1976 Apr 12	946274
Dantrolene-associated hepatic injury. Incidence and character.	1977 Apr	838213
Pleuropericardial reaction to treatment with dantrolene.	1979 Dec 21	501885
Dantrolene and suxamethonium. The effect of pre-operative dantrolene on the action of suxamethonium.	1979 Feb	375768
Treatment of neuroleptic malignant syndrome with dantrolene.	1982 Jul 3	6123782
Prevention of amphotericin B-induced rigors by dantrolene.	1986 Aug	3729640
Successful treatment of levodopa-induced neuroleptic malignant syndrome (NMS) and disseminated intravascular coagulation (DIC) in a patient with Parkinson's disease.	1992 Nov	1295627
Malignant hyperthermia induced by general anesthesia for bone marrow harvesting.	1997 Mar	9052921
Suxamethonium, masseter spasm and later malignant hyperthermia.	1998 Nov	10023282
Neuroleptic malignant syndrome after venlafaxine.	2000 Jan 22	10675082
Dantrolene reduces serum TNFalpha and corticosterone levels and muscle calcium, calpain gene expression, and protein breakdown in septic rats.	2001 Mar	11236903
Drug-induced liver injury.	2004 Mar 1	14986274
Prevention of acute adriamycin cardiotoxicity by dantrolene in rats.	2004 May	15222403
Non-paracetamol drug-induced fulminant hepatic failure among adults in Scotland.	2005 Feb	15674093
Prediction of genotoxicity of chemical compounds by statistical learning methods.	2005 Jun	15962942
An unusual case of Dantrolene sodium-induced urinary retention in post-traumatic minimally responsive state.	2005 Nov	16263650
Prevention of succinylcholine-induced fasciculation and myalgia: a meta-analysis of randomized trials.	2005 Oct	16192781
Early bicarbonate loading and dantroline for ziprasidone/haloperidol-induced neuroleptic malignant syndrome.	2006 Apr	16669738
Doxorubicin-induced reactive oxygen species generation and intracellular Ca2+ increase are reciprocally modulated in rat cardiomyocytes.	2006 Oct 31	17079870
KATP channel knockout worsens myocardial calcium stress load in vivo and impairs recovery in stunned heart.	2007 Apr	17189350
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
Pharmacologic profiling of human and rat cytochrome P450 1A1 and 1A2 induction and competition.	2008 Dec	18493746
Cellular imaging predictions of clinical drug-induced liver injury.	2008 Sep	18524759
Antispasmodic effect of shakuyakukanzoto extract on experimental muscle cramps in vivo: role of the active constituents of Glycyrrhizae radix.	2013 Jan 9	23164761

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

Official Name

English

DANTROLENE [USP-RS]

Common Name

English

DANTROLENE [USAN]

Common Name

English

Dantrolene [WHO-DD]

Common Name

English

2,4-IMIDAZOLIDINEDIONE, 1-(((5-(4-NITROPHENYL)-2-FURANYL)METHYLENE)AMINO)-

Systematic Name

English

dantrolene [INN]

Common Name

English

DANTROLENE [VANDF]

Common Name

English

DANTROLENE [HSDB]

Common Name

English

DANTROLENE [MI]

Common Name

English

1-(((5-(4-NITROPHENYL)-2-FURYL)METHYLENE)AMINO)IMIDAZOLIDINE-2,4-DIONE

Systematic Name

English

Classification Tree Code System Code

NDF-RT

N0000175735