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
Fairly rapidly absorbed, however, the extent of oral absorption is not known.
Ethotoin is fairly rapidly absorbed from the GI tract following oral administration; the extent of absorption is not known.
Therapeutic serum concentrations range from 15 to 50 ug/mL (74 to 245 umol/L) for ethotoin.
Ethotoin and phenytoin are distributed into breast milk...
Limited data suggest that ethotoin and, to a lesser degree, 5-phenylhydantoin (the N-deethylated metabolite) may exhibit nonlinear pharmacokinetics following oral administration of single 500-, 1000-, and 1500-mg doses of ethotoin. The degree of nonlinearity may increase following oral administration of multiple doses (with a dosing interval of 4-6 hours) of ethotoin when compared with single doses, probably secondary to accumulation of the drug in plasma.
For more Absorption, Distribution and Excretion (Complete) data for ETHOTOIN (9 total), please visit the HSDB record page.

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Metabolism / Metabolites
Hepatic. The drug exhibits saturable metabolism with respect to the formation of N-deethyl and p-hydroxyl-ethotoin, the major metabolites.
Ethotoin is metabolized by the liver to p-hydroxylated and m-hydoxylated derivatives following N-deethylation; these metabolites are conjugated with glucuronic acid. The N-deethylated metabolite may also be metabolized to 2-phenylhydantoic acid. Ethotoin appears to exhibit saturable metabolism with respect to the formation of the p-hydroxylated and N-deethylated metabolites.
The rate of hepatic biotransformation is increased in younger children, in pregnant women, in women during menses, and in patients with acute trauma; rate decreases with advancing age. /Hydantoin anticonvulsants/
The urinary excretion pattern of ethotoin and five metabolites were examined in three patients receiving continuous treatment with ethotoin at two dose levels, in order to investigate the mechanism behind the dose-dependent kinetics of this anticonvulsant drug. The results suggest a partial saturation in the dealkylation process at high dose levels in three patients. A rough approximation of the Michaelis-Menten constants for different enzymatic processes was attempted. On the basis of the results obtained, the p-hydroxylation may be a saturable process. The dose-dependent kinetics of ethotoin in man seem to be explicable by the existence of partly saturable enzymatic pathways.
Hepatic. The drug exhibits saturable metabolism with respect to the formation of N-deethyl and p-hydroxyl-ethotoin, the major metabolites.
Half Life: 3 to 9 hours

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Biological Half-Life
3 to 9 hours
At plasma concentrations less than about 8 ug/mL, ethotoin reportedly has an elimination half-life of 3-9 hours.
Ethotoin administration was 25 mg per kilogram in 5 patients. Ethotoin Tmax was 2 hours, with a T 1/2 of 5 hours. Saliva accurately represented the unbound fraction for ... /ethotoin/. Mean salivary levels (as percentage of total levels) were ... 54% for ethotoin.

Toxicity Summary
The mechanism of action is probably very similar to that of phenytoin. The latter drug appears to stabilize rather than to raise the normal seizure threshold, and to prevent the spread of seizure activity rather than to abolish the primary focus of seizure discharges. Ethotoin inhibits nerve impulses in the motor cortex by lowering sodium ion influx, limiting tetanic stimulation.

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Interactions
Risk of hepatotoxicity from a single toxic dose or prolonged use of acetaminophen may be increased and therapeutic efficacy may be decreased in patients regularly taking other hepatic enzyme-inducing agents such as phenytoin. /Hydantoin anticonvulsants/
Concurrent use of alcohol or CNS depression-producing medications with hydantoin anticonvulsants may enhance CNS depression. Chronic use of alcohol may decrease serum concentrations and effectiveness of hydantoins; concurrent use of hydantoin anticonvulsants with acute alcohol intake may increase serum hydantoin concentrations. /Hydantoin anticonvulsants/
Concurrent use of amiodarone with phenytoin and possibly with other hydantoin anticonvulsants may increase plasma concentrations of the hydantoin, resulting in increased effects and/or toxicity. /Hydantoin anticonvulsants/
Concurrent use with coumarin- or indandione-derivative anticoagulants, chloramphenicol, cimetidine, disulfiram, influenza virus vaccine, isoniazid, methylphenidate, phenylbutazone, ranitidine, salicylates, or sulfonamide may increase serum concentrations of hydantoin anticonvulsants because of decreased metabolism, thereby increasing the hydantoins' effects and/or toxicity. /Hydantoin anticonvulsants/
For more Interactions (Complete) data for ETHOTOIN (22 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Mouse sc 1060 mg/kg
LD50 Mouse ip 923 mg/kg
LD50 Rat sc 1000 mg/kg
LD50 Rat ip 625 mg/kg
LD50 Rat oral 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 that is hydantoin substituted by ethyl and phenyl at positions 3 and 5, respectively. An antiepileptic, it is less toxic than phenytoin but also less effective. It has a role as an anticonvulsant.
Ethotoin is a hydantoin derivative and anticonvulsant. Ethotoin exerts an antiepileptic effect without causing general central nervous system depression. The mechanism of action is probably very similar to that of phenytoin. The latter drug appears to stabilize rather than to raise the normal seizure threshold, and to prevent the spread of seizure activity rather than to abolish the primary focus of seizure discharges. Ethotoin is no longer commonly used.
Ethotoin is an Anti-epileptic Agent. The physiologic effect of ethotoin is by means of Decreased Central Nervous System Disorganized Electrical Activity.
Ethotoin is a hydantoin anticonvulsant with anti-epileptic activity. The mechanism of action is not completely known, but is thought to be fairly similar to phenytoin. Ethotoin influences synaptic transmission by altering sodium and calcium ion influx across neuronal membranes in the repolarization, depolarization, and membrane stability phase and interferes with the calcium uptake in presynaptic terminals. This inhibits neuronal firing and results in the stabilization of neuronal membranes, thereby preventing the spread of seizure activity at the motor cortex.
Ethotoin is a hydantoin derivative and anticonvulsant. Ethotoin exerts an antiepileptic effect without causing general central nervous system depression. The mechanism of action is probably very similar to that of phenytoin. The latter drug appears to stabilize rather than to raise the normal seizure threshold, and to prevent the spread of seizure activity rather than to abolish the primary focus of seizure discharges. Ethotoin is no longer commonly used.

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Drug Indication
For the control of tonic-clonic (grand mal) and complex partial (psychomotor) seizures.

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Mechanism of Action
The mechanism of action is probably very similar to that of phenytoin. The latter drug appears to stabilize rather than to raise the normal seizure threshold, and to prevent the spread of seizure activity rather than to abolish the primary focus of seizure discharges. Ethotoin inhibits nerve impulses in the motor cortex by lowering sodium ion influx, limiting tetanic stimulation.
The mechanism of action is not completely known, but it is thought to involve stabilization of neuronal membranes at the cell body, axon, and synapse and limitation of the spread of neuronal or seizure activity. ... Hydantoin anticonvulsants have an excitatory effect on the cerebellum, activating inhibitory pathways that extend to the cerebral cortex. This effect may also produce a reduction in seizure activity that is associated with an increased cerebellar Purkinje cell discharge. /Hydantoin anticonvulsants/

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Therapeutic Uses
Anticonvulsants
Hydantoin anticonvulsants are indicated in the suppression and control of tonic-clonic (grand mal) and simple or complex partial (psychomotor or temporal lobe) seizures. Ethotoin may be administered as a second-line agent when seizures have not been adequately controlled by the primary anticonvulsants and before proceeding to more toxic anticonvulsants. /Hydantoin anticonvulsants; Included in US product labeling./
Hydantoin anticonvulsants are not indicated in the treatment of absence (petit mal) seizures, or as first-line treatment of febrile, hypoglycemic, or other metabolic seizures. When tonic-clonic (grand mal) seizures coexist with absence seizures, combined therapy may be necessary. /Hydantoin anticonvulsants; NOT included in US product label/
Ethotoin may be substituted for phenytoin without loss of seizure control for improvement of gum hyperplasia, or other side effects, during anticonvulsant therapy. Ethotoin doses are usually 4 to 6 times greater than those of phenytoin. /NOT included in US product label/

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Drug Warnings
Ethotoin is contraindicated in patients with hepatic abnormalities or hematologic disorders.
Although the etiologic role of ethotoin has not been definitely established, blood dyscrasias have been reported in patients receiving the drug, and clinicians should be alert to the possibility of their occurrence. Patients should be advised to report immediately any sign or symptom indicative of hematologic toxicity (e.g., sore throat, fever, malaise, petechiae, easy bruising, epistaxis). Complete blood cell counts should be performed before and at monthly intervals for several months after initiation of ethotoin therapy. The drug should be discontinued if marked depression of blood cell count occurs.
Liver function tests should be performed in patients receiving ethotoin if there is clinical evidence of possible hepatic dysfunction. If signs of hepatotoxicity occur during ethotoin therapy, the drug should be discontinued.
Ataxia and gingival hyperplasia have been reported only rarely during ethotoin therapy and usually only in patients receiving an additional hydantoin derivative. When ethotoin has replaced other hydantoin-derivative anticonvulsants, both of these reactions have subsided in some patients.
For more Drug Warnings (Complete) data for ETHOTOIN (16 total), please visit the HSDB record page.

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Pharmacodynamics
Ethotoin is a hydantoin derivative and anticonvulsant. Ethotoin exerts an antiepileptic effect without causing general central nervous system depression. The mechanism of action is probably very similar to that of phenytoin. The latter drug appears to stabilize rather than to raise the normal seizure threshold, and to prevent the spread of seizure activity rather than to abolish the primary focus of seizure 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.)