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%. The drug is absorbed slowly and incompletely from the gastrointestinal tract, but sufficiently to maintain dose-related plasma concentrations. The mean half-life of the drug after an adult administration of 100 mg is approximately 9 hours. The drug is slowly metabolized in the liver, and its 5-hydroxy and acetaminophen metabolites are excreted in the urine along with the parent drug. Metabolism/Metabolites Metabolized primarily in the liver, most likely by hepatic microsomal enzymes. Its main metabolites in body fluids are 5-hydroxydanthralin and the acetaminophen metabolite of danthralin. Another metabolite of unknown structure appears to be associated with the latter. Danthralin may also be hydrolyzed, subsequently oxidized to nitrophenylfuran. Danthralin is metabolized by the hepatic mixed-function oxidase system to 5-hydroxydanthralin, which is conjugated with glucuronic acid or sulfate. It is also metabolized by nitroreductases to aminodanthralin, which inhibits the hepatic mixed-function oxidase system. Acetylation of aminodanthralin can block its inhibition. The intermediate products of the nitroreductase pathway form glucuronide and thiouric acid conjugates. The thiouric acid conjugation reaction is the detoxification mechanism of dantrolene's electrophilic metabolites.

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Biological Half-Life
The mean biological half-life after intravenous injection is 4 to 8 hours under most experimental conditions, while the half-life of an oral dose of 100 mg is 8.7 hours.

Hepatotoxicity
Mild, asymptomatic elevations of serum transaminases during dantrolene treatment are relatively rare (1%), but clinically observable liver injury is estimated to occur in 1 to 2 cases per 1,000 treated patients (0.1% to 0.2%). Liver injury can be severe; cases of acute liver failure and even death have been reported (Case 1). The incubation period for clinically observable liver injury is one week to several months, but it usually occurs within the first 6 months after the start of treatment (Case 2). More severe cases typically have a rapid onset with jaundice, nausea, and fatigue, and the condition progresses rapidly. Allergic reactions such as fever, rash, and eosinophilia, as well as autoimmune features, are rare. Enzyme elevations are primarily hepatocellular. Liver histology shows lesions similar to those of acute hepatitis. Complete recovery usually occurs within 1 to 3 months. Women, the elderly, and patients taking higher doses of dantrolene appear to be more susceptible to dantrolene hepatotoxicity. Probability score: A (Identified clinically significant cause of liver injury). Effects During Pregnancy and Lactation ◉ Overview of Use During Lactation
Because there is no information on long-term use of dantraline during lactation, alternative medications may be preferred, especially when breastfeeding newborns or premature infants. After short-term use, the drug is expected to be cleared from breast milk within 1 to 2 days. ◉ Effects on Breastfed Infants
No published information found as of the revision date. ◉ Effects on Lactation and Breast Milk
No published information found as of the revision date. Protein Binding
Significant, primarily binding to albumin. Interactions
The central effects of dantraline may be enhanced by sedative and anxiolytic 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 (soluble in DMF aqueous solution). (NTP, 1992)
Dantrroline is chemically a hydantoin derivative, but unlike other hydantoin derivatives (such as phenytoin), it does not have antiepileptic activity.
Dantrroline is a skeletal muscle relaxant. Its physiological action is achieved by reducing skeletal muscle contraction and tone.
Dantrroline is a muscle relaxant used to treat chronic spasticity. Unlike other commonly used muscle relaxants, it acts on peripheral muscles, not the central nervous system, such as the spinal cord or brain. Dantrolene can cause acute liver injury, which can be severe and even fatal.
Dantrroline is a hydantoin derivative and a muscle relaxant that acts directly on skeletal muscle. It inhibits excitation-contraction coupling in skeletal muscle by binding to rennet receptor 1, which reduces intracellular calcium ion concentration. Rennet receptors mediate the release of calcium ions from the sarcoplasmic reticulum, a key step in muscle contraction.
Dantrolene is a skeletal muscle relaxant whose mechanism of action is by interfering with excitation-contraction coupling of muscle fibers. It is used to treat spasticity and other neuromuscular abnormalities. Although its mechanism of action may not be central, dantrolene is generally classified as a central muscle relaxant.
See also: Dantrolene sodium (salt form).
Indications

For the treatment of fulminant skeletal muscle hypermetabolic events characteristic of malignant febrile crisis in patients of all ages, in conjunction with appropriate supportive care. Dantrolene is also used preoperatively and sometimes postoperatively to prevent or reduce the clinical and laboratory signs of malignant febrile crisis in individuals considered susceptible to it.
Mechanism of Action

Dantrolene inhibits excitation-contraction coupling of skeletal muscle by binding to rennet receptor 1, thereby reducing intracellular calcium ion concentration. Rennet receptors mediate the release of calcium ions from the sarcoplasmic reticulum, a key step in muscle contraction.
Dantrolene, acting directly on excitation-contraction coupling, may exert a relaxing effect and reduce skeletal muscle contraction by decreasing the amount of calcium ions released from the sarcoplasmic reticulum.
…It does not preferentially impair polysynaptic reflexes like central muscle relaxants. Dantrolene attenuates the intensity of electrically induced muscle twitches…without altering muscle action potentials…and/and/its inhibitory effect on reflexive contractions is greater than its inhibitory effect on voluntary contractions. …It does not affect neuromuscular transmission, nor…alter the potential properties of skeletal muscle cell membranes. Spasticity symptoms in patients with upper motor neuron injury are usually reduced…and functional abilities are often improved.
Dantrolene and 5-hydroxydantrolene inhibited rat muscle contraction responses in a dose-dependent manner both in vivo and in vitro. 5-hydroxydantrolene is less potent than dantrolene.
Dantrolene inhibits the release of calcium ions (Ca2+) from the sarcoplasmic reticulum in frog muscles.
In rat diaphragm pretreatment, dantrolene had no effect on 2,4-dinitrophenol-induced contractions but significantly reduced K+-induced contractions. The primary action of dantrolene appears to be in the sarcolemma, which may be the site of malignant hyperthermia. Adding dantrolene to the pretreatment of voltage-clamped myelinated frog nerve fibers shifts the potential-dependent parameter describing sodium ion (Na+) permeability towards a more negative membrane potential. Clearly, the negative surface charge of the membrane changes.
Therapeutic Uses
Central Muscle Relaxant Dantrolene significantly and persistently reduces spasticity and improves function in most paraplegic and hemiplegic patients; clonus, mass reflex movements, and abnormal resistance to passive traction are all reduced. Approximately half of patients with choreoathetoid cerebral palsy or multiple sclerosis experience significant improvement… …It has an adjunctive effect in the preoperative and postoperative management of malignant hyperthermia. It also has some benefit for patients with hypertonia of the external sphincter, excessive residual urine volume, and high urethral pressure. /Dantrolene Sodium/
Once malignant hyperthermia syndrome is diagnosed, intravenous injection should be administered immediately; ...Continue medication for 1 to 3 days to prevent recurrence.../Dantrolene Sodium/
For more complete data on the therapeutic uses of dantrolene (9 types in total), please visit the HSDB record page.

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Drug Warnings
...It/is likely to cause generalized muscle weakness, which may be detrimental to functional improvement. Patients should avoid driving or engaging in hazardous occupations. Patients with impaired lung function or severe myocardial disease should use dantrolene with caution.
Dantrolene is contraindicated in patients with liver disease...and in patients whose use of dantrolene causes severe postural abnormalities. Patients with peptic ulcers may need to discontinue dantrolene.
Dantrolene is not suitable for fibromyalgia, rheumatoid spondylitis, bursitis, arthritis, or localized acute muscle spasms. ...This product should not be used in patients with amyotrophic lateral sclerosis (ALS) because these patients have extremely low tolerance to the muscle weakness caused by dantrolene. ...Hepatocellular damage...can be fatal in some cases. The risk appears to be highest in patients over 30 years of age, especially women over 35 years of age who take more than 300 mg daily for 60 days or longer. Routine baseline liver function tests should be performed before treatment, and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) and alkaline phosphatase levels should be measured monthly during treatment. /Dantrolene Sodium/
While fatigue may be transient or mild, its persistence in some outpatients may affect treatment efficacy. Diarrhea in some patients can usually be controlled by gradually increasing the dose, but sometimes discontinuation may be necessary.
For more complete data on drug warnings for dantrolin (7 of 7), please visit the HSDB record page.

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Pharmacodynamics
Dantrolene is a direct-acting skeletal muscle relaxant. It is currently the only drug specifically effective against malignant hyperthermia. In isolated neuromuscular specimens, dantrolin has been shown to produce a relaxing effect by affecting muscle contractile responses outside of the neuromuscular junction. In skeletal muscle, tantrolin can dissociate excitation-contraction coupling, possibly by interfering with the release of Ca²⁺ from the sarcoplasmic reticulum. Evidence suggests intrinsic abnormalities in skeletal muscle tissue in anesthesia-induced malignant hyperthermia. In some populations, studies have hypothesized that triggering agents (such as general anesthetics and depolarizing neuromuscular blockers) induce intracellular changes leading to elevated sarcoplasmic calcium concentrations. This elevated sarcoplasmic calcium activates acute cellular catabolism, thereby triggering a malignant hyperthermic crisis. Some studies hypothesize that adding tantrolin to muscle cells in malignant hyperthermic syndrome induced by triggering agents could restore normal levels of ionized calcium in the sarcoplasm.

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.)