When given on day 18 of gestation, etoine (oral gavage; 600 mg/kg; once) causes modest mortality and weight loss in offspring [2].

Animal/Disease Models: Pregnant SD (SD (Sprague-Dawley)) CD rats [2]
Doses: 600 mg/kg
Route of Administration: po (oral gavage); 600 mg/kg;
Experimental Results: The mortality rate before weaning of ethotoin was 2.0%, ethotoin-exposed animals The body weight was approximately 6.6% lower than that of the control animals.

Absorption, Distribution and Excretion
Etotide sodium is rapidly absorbed, but the extent of oral absorption is unclear. After oral administration, phenytoin sodium is rapidly absorbed from the gastrointestinal tract; the extent of absorption is unclear. Therapeutic serum concentrations of phenytoin sodium range from 15 to 50 μg/mL (74 to 245 μmol/L). Etotide sodium and phenytoin sodium are distributed into breast milk… Limited data suggest that after a single oral dose of 500 mg, 1000 mg, and 1500 mg of phenytoin sodium, phenytoin sodium (and a lesser extent 5-phenylhydantoin, i.e., the N-deethyl metabolite) may exhibit nonlinear pharmacokinetics. The degree of nonlinearity may increase after multiple oral doses of phenytoin (dose intervals of 4–6 hours) compared to a single dose, possibly due to drug accumulation in plasma. For more complete data on the absorption, distribution, and excretion of phenytoin (9 items in total), please visit the HSDB record page.

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Metabolism/Metabolites
Hepatic metabolism. This drug exhibits saturated metabolism in the formation of its major metabolites, N-deethyletytoin and p-hydroxyetytoin.
Ethytoin is metabolized in the liver, with N-deethylation yielding p-hydroxylated and m-hydroxylated derivatives; these metabolites are conjugated with glucuronic acid. The N-deethylated metabolite may also be metabolized to 2-phenylhydantoin. Ethytoin sodium appears to exhibit saturated metabolism in the formation of p-hydroxylated and N-deethylated metabolites.
Hepatic biotransformation is increased in young children, pregnant women, menstruating women, and patients with acute trauma; the biotransformation decreases with age. /Hydantoin anticonvulsants/
To investigate the mechanism of dose-dependent kinetics of this anticonvulsant, we performed urinary excretion patterns of ethytoin sodium and its five metabolites in three patients receiving consecutive treatment at two dose levels of ethytoin sodium. The results showed that in all three patients, the dealkylation process was partially saturated at high dose levels. We attempted to roughly estimate the Michaelis constants for different enzymatic processes. Based on the results, hydroxylation may be a saturation process. The dose-dependent kinetics of etorutin in humans appear to be explained by the presence of a partially saturated enzymatic pathway. Hepatic metabolism: The drug exhibits saturated metabolism in the formation of its main metabolites, N-desethyletorutin and p-hydroxyetorutin. Half-life: 3 to 9 hours. Biological half-life: 3 to 9 hours. It has been reported that the elimination half-life of etorutin is 3–9 hours when plasma concentrations are below approximately 8 μg/mL. In 5 patients, etorutin was administered at a dose of 25 mg/kg. The time to peak concentration (Tmax) of etorutin was 2 hours, and the half-life (T1/2) was 5 hours. Saliva accurately reflects the free fraction of etorutin. The mean salivary concentration of etorutin (as a percentage of total concentration) was 54%.

Toxicity Summary
Its mechanism of action may be very similar to phenytoin. Phenytoin appears to stabilize rather than raise the normal seizure threshold and prevent the spread of epileptic activity rather than eliminate the primary focus of epileptic discharge. Ethyltoin inhibits nerve impulses in the motor cortex by reducing sodium ion influx, thereby limiting tonic stimulation. Interactions For patients who frequently take other liver enzyme inducers (e.g., phenytoin), a single toxic dose or prolonged use of acetaminophen may increase the risk of hepatotoxicity and reduce treatment efficacy. /Phenytoin Anticonvulsants/ Concomitant use of alcohol or central nervous system depressants may enhance the central nervous system depressant effects of phenytoin anticonvulsants. Prolonged alcohol consumption may decrease serum concentrations and efficacy of phenytoin-like drugs; concomitant use of phenytoin anticonvulsants and acute alcohol intake may increase serum phenytoin concentrations. /Phenytoin Anticonvulsants/
Concomitant use of amiodarone with phenytoin sodium and other phenytoin anticonvulsants may increase plasma concentrations of phenytoin, thereby enhancing its effects and/or toxicity. /Phenytoin Anticonvulsants/
Concomitant use of coumarin or indanedione derivative anticoagulants, chloramphenicol, cimetidine, disulfiram, influenza virus vaccine, isoniazid, methylphenidate, phenylbutazone, ranitidine, salicylates, or sulfonamides may increase serum concentrations of phenytoin anticonvulsants due to slowed metabolism, thereby enhancing their effects and/or toxicity. /Hydroxyureas Anticonvulsants/
For more complete data on interactions of hydroxyureas (22 in total), please visit the HSDB record page.

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Non-human toxicity values
Mouse subcutaneous injection LD50: 1060 mg/kg
Mouse intraperitoneal injection LD50: 923 mg/kg
Rat subcutaneous injection LD50: 1000 mg/kg
Rat intraperitoneal injection LD50: 625 mg/kg
Rat oral LD50: 1500 mg/kg

[1]. A S Troupin, et al. Clinical pharmacology of mephenytoin and ethotoin. Ann Neurol. 1979 Nov;6(5):410-4.
[2]. D R Minck, et al. Comparison of the behavioral teratogenic potential of phenytoin, mephenytoin, ethotoin, and hydantoin in rats. Teratology. 1991 Apr;43(4):279-93.

Ethotoin is an imidazolidine-2,4-dione compound, a derivative of hydantoin with ethyl and phenyl substitutions at the 3 and 5 positions, respectively. It is an antiepileptic drug, less toxic than phenytoin, but with lower efficacy. It has anticonvulsant activity. Ethotoin is a derivative of hydantoin and is also an anticonvulsant. Ethotoin exerts its antiepileptic effect without causing central nervous system depression. Its mechanism of action may be very similar to phenytoin. Phenytoin appears to stabilize rather than raise the normal seizure threshold and prevent the spread of epileptic activity rather than eliminating the primary focus of epileptic discharge. Ethotoin is no longer commonly used. Ethotoin is an antiepileptic drug. The physiological effect of Ethotoin is achieved by reducing disordered electrical activity in the central nervous system. Ethotoin is a phenytoin-class anticonvulsant with antiepileptic activity. Its mechanism of action is not fully elucidated, but is considered very similar to phenytoin. Etotide affects synaptic transmission by altering sodium and calcium ion influxes into the neuronal membrane during repolarization, depolarization, and membrane stabilization phases, and interferes with calcium uptake at presynaptic terminals. This inhibits neuronal firing, thereby stabilizing the neuronal membrane and preventing the spread of epileptic activity to the motor cortex. Etotide is a phenytoin derivative and also an anticonvulsant. Etotide exerts its antiepileptic effect without causing overall central nervous system depression. Its mechanism of action may be very similar to that of phenytoin. The latter appears to stabilize rather than raise the normal seizure threshold and prevent the spread of epileptic activity rather than eliminate the primary focus of epileptic discharge. Etotide sodium is no longer commonly used. Drug Indications For the control of tonic-clonic (grand mal) and complex partial (psychomotor) seizures. Mechanism of Action Its mechanism of action may be very similar to that of phenytoin sodium. The latter appears to stabilize rather than raise the normal seizure threshold and prevent the spread of epileptic activity rather than eliminate the primary focus of epileptic discharge. Etotide sodium inhibits nerve impulses in the motor cortex by reducing sodium ion influx, thereby limiting tonic stimulation. Its mechanism of action is not fully understood, but it is believed to be related to stabilizing neuronal membranes at cell bodies, axons, and synapses, and limiting neuronal activity or the spread of seizures. ...Phenytoin anticonvulsants have an excitatory effect on the cerebellum, activating inhibitory pathways extending to the cerebral cortex. This effect may also reduce seizure activity associated with increased Purkinje cell firing in the cerebellum. /Phenytoin Anticonvulsants/

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Therapeutic Use
Anticonvulsants
Phenytoin anticonvulsants are indicated for the suppression and control of tonic-clonic (grand mal) and simple or complex partial (psychomotor or temporal lobe) seizures. Etotide sodium can be used as a second-line treatment when first-line antiepileptic drugs fail to effectively control seizures and before considering more toxic antiepileptic drugs. /Phenytoin antiepileptic drugs; listed on US product labels. Phenytoin-type antiepileptic drugs are not indicated for the treatment of absence seizures (petit mal seizures) or as first-line treatment for febrile seizures, hypoglycemic seizures, or other metabolic seizures. Combination therapy may be necessary when tonic-clonic seizures (grand mal seizures) coexist with absence seizures. /Phenytoin-type antiepileptic drugs; not listed on the US product label. /If gingival hyperplasia or other side effects occur during antiepileptic drug treatment, etorutin sodium can be used as an alternative to phenytoin sodium without affecting seizure control. The dosage of etorutin sodium is typically 4 to 6 times that of phenytoin sodium. /Not included on the US product label/

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Drug Warnings
Ethotoin sodium is contraindicated in patients with abnormal liver function or hematologic disorders.
Although the pathogenesis of etorutin sodium is not fully understood, there have been reports of hematologic disorders in patients taking this drug, and clinicians should be alert to the possibility of its occurrence. Patients should be informed to report any signs or symptoms suggestive of hematologic toxicity (e.g., sore throat, fever, malaise, petechiae, easy bruising, nosebleeds) immediately. A complete blood count should be performed monthly before starting etorutin sodium treatment and for several months afterward. If a significant decrease in blood cell count occurs, the medication should be discontinued. If clinical signs of liver dysfunction appear, liver function tests should be performed in patients taking etorutin sodium. If signs of hepatotoxicity occur during etorutin treatment, the medication should be discontinued immediately. Rare reports of ataxia and gingival hyperplasia during etorutin treatment are observed, and usually only in patients taking other hydantoin drugs concurrently. In some patients, both of these reactions have resolved when etorutin replaces other hydantoin anticonvulsants. For more complete data on etorutin warnings (16 in total), please visit the HSDB records page.

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Pharmacodynamics
Ethioprine is a hydantoin anticonvulsant. Ethioprine has antiepileptic effects but does not cause central nervous system depression. Its mechanism of action may be very similar to that of phenytoin. The latter drug appears to stabilize rather than raise the normal seizure threshold and to prevent the spread of epileptic activity rather than eliminate the main focus of epileptic discharges.

C11H12N2O2

204.22518

204.09

C, 64.69; H, 5.92; N, 13.72; O, 15.67

86-35-1

Ethotoin-d5;2714409-09-1

3292

Stout prisms from water.

1.197 g/cm1.197 g/cm3

342.72°C (rough estimate)

94ºC

1.555

0.877

1

2

2

15

272

0

O=C1N(CC)C(=O)C(C2C=CC=CC=2)N1

SZQIFWWUIBRPBZ-UHFFFAOYSA-N

InChI=1S/C11H12N2O2/c1-2-13-10(14)9(12-11(13)15)8-6-4-3-5-7-8/h3-7,9H,2H2,1H3,(H,12,15)

3-ethyl-5-phenylimidazolidine-2,4-dione

Ethotoin, Peganone.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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

DMSO : ≥ 100 mg/mL (~489.64 mM)

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.)