Drug compounds have included stable heavy isotopes of carbon, hydrogen, and other elements, mostly as quantitative tracers while the drugs were being developed. Because deuteration may have an effect on a drug's pharmacokinetics and metabolic properties, it is a cause for concern [1].

Absorption, Distribution and Excretion
Bioavailability is 70%.
ABSORPTION...FROM GI TRACT IS SLOW & INCOMPLETE BUT SUFFICIENTLY CONSISTENT TO PROVIDE DOSE-RELATED PLASMA CONCN. MEAN HALF LIFE OF DRUG IN ADULTS IS ABOUT 9 HR AFTER 100-MG DOSE. IT IS SLOWLY METABOLIZED BY LIVER, & THE 5-HYDROXY & ACETAMIDO METABOLITES ARE EXCRETED WITH UNCHANGED DRUG IN URINE.

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Metabolism / Metabolites
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.
DANTROLENE IS METABOLIZED BY THE HEPATIC MIXED FUNCTION OXIDASE SYSTEM TO 5-HYDROXYDANTROLENE WHICH IS CONJUGATED WITH GLUCURONIC ACID OR WITH SULFATE. IT IS ALSO METABOLIZED BY NITROREDUCTASE TO AMINODANTROLENE WHICH INHIBITS THE HEPATIC MIXED FUNCTION OXIDASE SYSTEM. ACETYLATION OF AMINODANTROLENE BLOCKS THE INHIBITORY EFFECTS. INTERMEDIATES IN THE NITROREDUCTASE PATHWAY FORM GLUCURONIDE & MERCAPTURIC ACID CONJUGATES. THE MERCAPTURIC ACID CONJUGATION REACTION IS A DETOXIFICATION MECHANISM FOR AN ELECTROPHILIC METABOLITE OF DANTROLENE.

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Biological 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.

Hepatotoxicity
Mild, asymptomatic serum aminotransferase elevations during dantrolene therapy are relatively uncommon (1%), but clinically over liver injury is estimated to occur in 1 to 2 per thousand treated persons (0.1% to 0.2%). The liver injury can be severe; cases of acute liver failure and even death have been described (Case 1). The latency to onset of clinically apparent liver injury ranges from one week to several months, but is usually within the first 6 months of starting therapy (Case 2). More serious cases are associated with a sudden onset with jaundice, nausea and fatigue, and rapid progression. Allergic manifestations such as fever, rash and eosinophilia are rare, as are autoimmune features. The pattern of enzyme elevations is predominantly hepatocellular. Liver histology demonstrates an acute-hepatitis like picture. Recovery is usually complete within 1 to 3 months. Women, the elderly, and patients taking higher doses appear to be more susceptible to developing dantrolene hepatotoxicity.
Likelihood score: A (Well established cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because no information is available on the long-term use of dantrolene during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. After short-term use, the drug would be expected to be eliminated from milk in 1 to 2 days.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Significant, mostly to albumin.

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Interactions
CENTRAL EFFECTS OF DANTROLENE MAY BE ENHANCED BY SEDATIVE-ANTIANXIETY DRUGS.

[1]. Impact of Deuterium Substitution on the Pharmacokinetics of Pharmaceuticals. Ann Pharmacother. 2019 Feb;53(2):211-216.

[2]. The effect of dantrolene sodium on rat skeletal muscle in relation to the plasma concentration. Eur J Pharmacol. 1979 Feb 1;53(4):335-42.

[3]. Dantrolene inhibition of ryanodine receptor Ca2+ release channels. Molecular mechanism and isoform selectivity. J Biol Chem. 2001 Apr 27;276(17):13810-6.

[4]. Dantrolene inhibits human erythrocyte glutathione reductase. Biol Pharm Bull. 2008 Nov;31(11):2036-9.

[5]. Dantrolene, a therapeutic agent for malignant hyperthermia, markedly improves the function of failing cardiomyocytes by stabilizing interdomain interactions within the ryanodine receptor. J Am Coll Cardiol. 2009 May 26;53(21):1993-2005.

[6]. Dantrolene is neuroprotective in Huntington's disease transgenic mouse model. Mol Neurodegener. 2011 Nov 25;6:81.

Crystals (in aqueous DMF). (NTP, 1992)
Chemically, dantrolene is a hydantoin derivative, but does not exhibit antiepileptic activity like other hydantoin derivates such as phenytoin.
Dantrolene is a Skeletal Muscle Relaxant. The physiologic effect of dantrolene is by means of Decreased Striated Muscle Contraction, and Decreased Striated Muscle Tone.
Dantrolene is a muscle relaxant used for treatment of chronic spasticity that differs from other commonly used muscle relaxants in acting peripherally on muscle, rather than centrally on the spinal cord or brain. Dantrolene can cause acute liver injury which can be severe and even fatal.
Dantrolene is a hydantoin derivative and direct-acting skeletal muscle relaxant. 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.
Skeletal muscle relaxant that acts by interfering with excitation-contraction coupling in the muscle fiber. It is used in spasticity and other neuromuscular abnormalities. Although the mechanism of action is probably not central, dantrolene is usually grouped with the central muscle relaxants.
See also: Dantrolene Sodium (has salt form).

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Drug 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.

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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.
DANTROLENE /PRODUCES RELAXATION &/ REDUCES CONTRACTION OF SKELETAL MUSCLE BY DIRECT ACTION ON EXCITATION-CONTRACTION COUPLING, PERHAPS BY DECR AMT OF CALCIUM RELEASED FROM SARCOPLASMIC RETICULUM. ...IT DOES NOT IMPAIR POLYSYNAPTIC REFLEXES PREFERENTIALLY AS DO CENTRALLY ACTING MUSCLE RELAXANTS. DANTROLENE DIMINISHES FORCE OF ELECTRICALLY INDUCED TWITCHES...WITHOUT ALTERING MUSCLE ACTION POTENTIALS.../&/ REDUCES REFLEX MORE THAN VOLUNTARY CONTRACTION. .../IT/ DOES NOT AFFECT NEUROMUSCULAR TRANSMISSION, NOR...CHANGE ELECTRICAL POTENTIAL PROPERTIES OF SKELETAL MUSCLE MEMBRANES. IN PATIENTS WITH UPPER MOTONEURON LESIONS, SPASTICITY IS GENERALLY DIMINISHED...& FUNCTIONAL CAPACITY IS OFTEN IMPROVED.
DANTROLENE & 5-HYDROXYDANTROLENE INHIBITED RAT MUSCLE CONTRACTION RESPONSES IN DOSE-DEPENDENT MANNER IN VIVO & IN VITRO. 5-HYDROXYDANTROLENE WAS LESS POTENT THAN DANTROLENE.
DANTROLENE INHIBITS CALCIUM 2+ ION (CA2+) RELEASE FROM THE SARCOPLASMIC RETICULUM OF FROG MUSCLE.
IN RAT DIAPHRAGM PREPN DANTROLENE HAD NO EFFECT ON CONTRACTURES INDUCED BY 2,4-DINITROPHENOL, BUT REDUCED SIGNIFICANTLY THE CONTRACTURE PRODUCED BY K+. THE MAJOR ACTION OF DANTROLENE APPEARS TO BE ON THE SARCOLEMMA, WHICH MAY BE THE SITE OF THE MALIGNANT HYPERPYREXIA ABNORMALITY.
DANTROLENE ADDED TO PREPN OF VOLTAGE-CLAMPED MYELINATED FROG NERVE FIBERS SHIFTED THE POTENTIAL-DEPENDENT PARAMETERS DESCRIBING SODIUM ION (NA+) PERMEABILITY TOWARDS MORE NEGATIVE MEMBRANE POTENTIALS. APPARENTLY, A CHANGE IN THE NEGATIVE SURFACE CHARGE OF THE MEMBRANE IS INDUCED.

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Therapeutic Uses
Muscle Relaxants, Central
DANTROLENE PROVIDES SIGNIFICANT & SUSTAINED REDUCTION OF SPASTICITY & IMPROVES FUNCTIONAL CAPACITY FOR MAJORITY OF PARAPLEGIC & HEMIPLEGIC PATIENTS; CLONUS, MASS-REFLEX MOVEMENTS & ABNORMAL RESISTANCE TO PASSIVE STRETCH ARE REDUCED. ABOUT 1/2 OF PT WITH ATHETOID CEREBRAL PALSY OR MULTIPLE SCLEROSIS ARE...SUFFICIENTLY IMPROVED...
.../ACTION HELPFUL/ FOR PRE- & POST OPERATIVE MANAGEMENT OF MALIGNANT HYPERTHERMIA. ...OF SOME BENEFIT IN PATIENTS WITH EXTERNAL SPHINCTER HYPERTONICITY WHO HAVE EXCESSIVE RESIDUAL URINE VOLUME & HIGH URETHRAL PRESSURE. /DANTROLENE SODIUM/
...SHOULD BE ADMIN IV AS SOON AS SYNDROME OF MALIGNANT HYPERTHERMIA IS RECOGNIZED; ... NECESSARY FOR 1 TO 3 DAYS TO PREVENT RECURRENCE... /DANTROLENE SODIUM/
For more Therapeutic Uses (Complete) data for DANTROLENE (9 total), please visit the HSDB record page.

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Drug Warnings
.../IT/ TENDS TO INDUCE GENERALIZED MUSCLE WEAKNESS THAT CAN BE DETRIMENTAL TO FUNCTIONAL IMPROVEMENT. ...PT SHOULD BE CAUTIONED AGAINST DRIVING OR PARTICIPATING IN HAZARDOUS OCCUPATIONS. ... DANTROLENE SHOULD BE USED WITH CAUTION IN PT WITH IMPAIRED PULMONARY FUNCTION OR SEVERE MYOCARDIAL DISEASE.
DANTROLENE IS CONTRAINDICATED IN LIVER DISEASE...& WHEN GROSS POSTURAL ABNORMALITIES RESULT FROM ITS USE. IT SHOULD PROBABLY BE WITHHELD IN PEPTIC ULCER PT.
DANTROLENE IS NOT INDICATED IN FIBROSITIS, RHEUMATOID SPONDYLITIS, BURSITIS, ARTHRITIS OR ACUTE MUSCLE SPASM OF LOCAL ORIGIN. .../IT/ SHOULD NOT BE GIVEN TO PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS, FOR THESE INDIVIDUALS HAVE VERY LOW TOLERANCE TO MUSCLE WEAKNESS INDUCED BY DANTROLENE. ...HEPATOCELLULAR INJURY...HAS BEEN FATAL IN SOME CASES. RISK APPEARS TO BE GREATEST IN PATIENTS OVER 30 YEARS, ESP WOMEN OVER 35 YEARS, WHO HAVE RECEIVED MORE THAN 300 MG DAILY FOR 60 DAYS OR LONGER. ...ROUTINE BASELINE HEPATIC FUNCTION STUDIES SHOULD BE PERFORMED PRIOR TO THERAPY, & SGOT OR SGPT & ALKALINE PHOSPHATASE LEVELS SHOULD BE DETERMINED MONTHLY DURING THERAPY. /DANTROLENE SODIUM/
ALTHOUGH WEAKNESS MAY BE TRANSIENT OR MILD, ITS PERSISTENCE IN SOME AMBULATORY PT MAY COMPROMISE THERAPEUTIC BENEFIT. ...DIARRHEA THAT OCCURS IN SOME PT CAN USUALLY BE CONTROLLED BY MORE GRADUAL INCR IN DOSAGE, IT MAY NECESSITATE WITHDRAWAL OF DRUG.
For more Drug Warnings (Complete) data for DANTROLENE (7 total), please visit the HSDB record page.

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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.

C14H10N4O5

314.253

317.075

1185234-99-4

Dantrolene;7261-97-4

6914273

Off-white to light yellow solid powder

534 to 536 °F (NTP, 1992)
279-280 °C
279 °C

2.477

1

6

3

23

524

0

C1C(=O)NC(=O)N1/N=C/C2=CC=C(O2)C3=CC=C(C=C3)[N+](=O)[O-]

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+

1-[(E)-[5-(4-nitrophenyl)furan-2-yl]methylideneamino]imidazolidine-2,4-dione

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)