During pregnancy, mephenytoin (drug, 100 mg/kg, 200 mg/kg) decreased mother weight gain and increased hybridization of offspring at 200 mg/kg but not at 100 mg/kg. Sprague-Dawley CD Mefentoin dramatically lowers blood cholesterol and triglyceride levels in mice and may have a hypolipidemic impact when administered intraperitoneally at a dose of 20 mg/kg per day for 16 consecutive days [3].

Absorption, Distribution and Excretion
1.4 L/kg Mephenytoin is absorbed via the gastrointestinal tract. After oral administration, the drug has an onset of action of 30 minutes and a duration of action of 24–48 hours. The plasma concentrations required to achieve therapeutic efficacy are unknown; however, it has been reported that total serum concentrations of 25–40 μg/mL of mephenytoin and its major metabolite effectively control seizures without causing clinical toxicity. When mephenytoin is used in combination with its active metabolite nilvano (SRP), the therapeutic serum concentration range is 25–40 μg/mL (115–183 μmol/L). The time to peak concentration of mephenytoin is 45 minutes to 4 hours, while that of nilvano is 16–36 hours. …A single-dose study of mephenytoin (Mephenytoin)… was conducted in adult hospitalized patients receiving stable therapy with other antiepileptic drugs. Five patients received mephenytoin at a dose of 7 mg per kilogram of body weight. Strictly continuous blood sampling was performed. The time to peak concentration (Tmax) of mephenytoin was 1 hour, and its half-life (T1/2) was 7 hours; the T1/2 of its metabolite, 5-ethyl-5-phenylhydantoin, was 96 hours. …Saliva accurately reflects the free concentrations of both drugs. The average salivary concentration of mephenytoin (as a percentage of total concentration) was 61%, and that of its metabolite was 73%… The therapeutic significance lies in the fact that after administration of mephenytoin, its metabolite, 5-ethyl-5-phenylhydantoin, exerts an anticonvulsant effect, and its long half-life allows for the maintenance of stable blood drug concentrations with a simple dosing regimen.

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Metabolism/Metabolites
Hepatic biotransformation rate is increased in infants, pregnant women, menstruating women, and patients with acute trauma; the conversion rate decreases with age. …The active metabolite of mephenytoin is nilvano (5-ethyl-5-phenylhydantoin). /Hydroxyhydantoin Anticonvulsants/
Mefphenytoin undergoes N-demethylation in the liver to produce the highly toxic compound 5,5-ethylphenylhydroxyurea. This metabolite may at least partially explain the therapeutic and toxic effects of mephenytoin. The N-demethylated metabolite may be excreted in the urine or further metabolized by the para-hydroxylation of the phenyl group, conjugated with glucuronic acid, and then excreted in the urine.
Human liver was used in studies of the para-hydroxylase in mephenytoin, an enzyme considered to be the cause of the genetic polymorphism in mephenytoin metabolism. Researchers developed a gas chromatography method to determine para-hydroxylation and N-demethylation (another major metabolic pathway). Both reactions are localized to the microsomal component and require NADPH. Studies showed that CO, SKF 525-A, and metheprone all inhibited the para-hydroxylation reaction. This led to the conclusion that some form of cytochrome P-450 catalyzes this reaction. Even at a substrate concentration of 500 μM, the rate of N-demethylation in the human liver did not reach saturation. However, the hydroxylation reaction followed Michaelis-Menten kinetics. Km values measured in five different livers ranged from 59 to 143 μM. The linearity of the Eadie-Hofstee plot was consistent with the involvement of a single catalytic site. The major metabolite of the antiepileptic drug mephenytoin (3-methyl-5-ethyl-5-phenylhydantoin) was identified in urine after a single oral dose of 100 mg mephenytoin in humans. Researchers used chemical synthesis, gas chromatography-mass spectrometry, and nuclear magnetic resonance spectroscopy to determine its chemical structure as 3-methyl-5-ethyl-5-(4-hydroxyphenyl)hydantoin (4-OH-M), which is the product of the aromatic hydroxylation of mephenytoin in humans. Quantitative determination of 4-OH-M in the urine of 10 volunteers showed that 43 ± 7% (SD) of the drug was excreted as a glucuronide of this metabolite after a single oral dose of 100 mg mephenytoin. The urinary excretion of the demethylated metabolite 5-ethyl-5-phenylhydantoin (Nirvanol) is very low (only 1% of the dose over 24 hours), highlighting the importance of 4-OH-M as the major metabolite following a single oral dose of mephenytoin. Under the selected conditions, no other hydroxylated products of mephenytoin (2-OH-M, E-OH-M, or aliphatic hydroxylated 2-OH-ethyl-M) were detected (less than 1 μmol/24 hours). For more complete metabolite/metabolite data on mephenytoin (6 metabolites in total), please visit the HSDB record page. Biological half-life: Approximately 7 hours… A single-dose study of mephenytoin… was conducted in hospitalized adult patients receiving stable therapy with other antiepileptic drugs. ...The time to peak concentration (Tmax) of mephenytoin is 1 hour, and its half-life (T1/2) is 7 hours; the T1/2 of its metabolite 5-ethyl-5-phenylhydantoin is 96 hours. ...
Approximately 7 hours, but for the active metabolite nilvano, approximately 95 to 144 hours.

Interactions
For patients who frequently take other liver enzyme inducers (e.g., phenytoin sodium), a single toxic dose or prolonged use of acetaminophen may increase the risk of hepatotoxicity and reduce its therapeutic effect. /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 anticonvulsants; concomitant use of phenytoin anticonvulsants and acute alcohol consumption may increase serum phenytoin concentrations. /Phenytoin Anticonvulsants/
Concomitant use of amiodarone and phenytoin sodium, and possibly in combination with other phenytoin anticonvulsants, may increase plasma concentrations of phenytoin, leading to enhanced efficacy and/or increased toxicity. Concomitant use of phenytoin-type anticonvulsants with coumarin or indanedione derivative anticoagulants, chloramphenicol, cimetidine, disulfiram, influenza virus vaccine, isoniazid, methylphenidate, phenylbutazone, ranitidine, salicylates, or sulfonamides may lead to increased serum concentrations of phenytoin-type anticonvulsants due to slowed metabolism, thereby enhancing the effects and/or toxicity of phenytoin-type anticonvulsants. Dosage adjustment of the anticonvulsants may be necessary. Furthermore, the anticoagulant effect of coumarin or indanedione derivative anticoagulants may initially be enhanced, but diminishes with continued concomitant use. /Phenytoin-type anticonvulsants/ For more complete data on interactions of phenytoin (23 in total), please visit the HSDB record page.

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Non-human toxicity values
Guinea pig oral LD50: 380 mg/kg
Rabbit oral LD50: 430 mg/kg
Cat LD50: 190 mg/kg
Mouse intraperitoneal LD50: 317 mg/kg
For more complete data on non-human toxicity values of phenytoin (7 in total), please visit the HSDB record page.

[1]. Assessment of urinary mephenytoin metrics to phenotype for CYP2C19 and CYP2B6 activity. Eur J Clin Pharmacol. 2008;64(4):387-398.

[2]. Comparison of the behavioral teratogenic potential of phenytoin, mephenytoin, ethotoin, and hydantoin in rats. Teratology. 1991 Apr;43(4):279-93.

[3]. Hypolipidemic activity of antiepileptic 5-phenylhydantoins in mice. Eur J Pharmacol. 1985 Oct 29;117(1):135-8.

Mephenytoin is an imidazolidine-2,4-dione (hydantoin) compound with a methyl group at the N-3 position and an ethyl or phenyl group at the C-5 position of the imidazolidine nucleus. It is an antiepileptic drug, currently discontinued in the US and UK, but still widely studied due to its interesting hydroxylation polymorphism. Mephenytoin has antiepileptic activity and is used to treat refractory partial epilepsy. Mephenytoin is a solid. This compound belongs to the phenylhydantoin class of compounds, which are heterocyclic aromatic compounds containing a phenyl-substituted imidazolidinedione moiety. Mephenytoin is known to target the α subunit of sodium channel protein type 5. Cytochrome P450 2C19, cytochrome P450 2C8, cytochrome P450 2C9, cytochrome P450 2B6, cytochrome P450 1A2, and cytochrome P450 2D6 are known to metabolize mephenytoin. Mephenytoin is a hydantoin anticonvulsant used to control various partial seizures. Compared to other anticonvulsants, mephenytoin and oxazolidinedione derivatives are associated with a higher incidence of hematologic disorders. Mephenytoin is an antiepileptic drug. Its physiological action is achieved by reducing disordered electrical activity in the central nervous system. Mephenytoin is a heterocyclic organic compound with anticonvulsant properties. Although its mechanism of action is not fully understood, mephenytoin sodium may promote sodium efflux from motor cortical neurons, thereby stabilizing the excitation threshold induced by overstimulation. Therefore, the drug reduces the membrane sodium ion gradient, preventing the spread of cortical epileptic signals. Due to its potential to cause hematologic disorders, it is only used after other less toxic antiepileptic drugs have failed. An antiepileptic drug effective against tonic-clonic epilepsy. It may cause hematologic disorders.

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Drug Indications
For the treatment of refractory partial epilepsy.

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Mechanism of Action
The mechanism of action of phenytoin is not fully understood, but numerous studies strongly suggest that its primary mechanism is the blocking of frequency-dependent, use-dependent, and voltage-dependent neuronal sodium channels, thereby limiting the repetitive firing of action potentials.
Its mechanism of action is not fully understood, but it is believed to involve stabilizing the neuronal membrane at the cell body, axon, and synapse, and limiting neuronal activity or the spread of seizures. …Phenytoin anticonvulsants have an excitatory effect on the cerebellum, activating inhibitory pathways that extend to the cerebral cortex. This effect may also lead to a reduction in seizure activity, which is associated with increased firing of Purkinje cells in the cerebellum. /Phenytoin Anticonvulsants/

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Therapeutic Uses
Anticonvulsants
Phenytoin anticonvulsants are indicated for the suppression and control of tonic-clonic (grand mal) and simple partial or complex partial (psychomotor or temporal lobe) seizures. …Phenytoin can also be used to treat patients with simple partial (focal and Jacksonian) seizures who are unresponsive to anticonvulsants with lower toxicity. /Phenytoin anticonvulsants; already listed on the US product label./
Phenytoin anticonvulsants are not indicated for the treatment of absence seizures (petit mal seizures) or as first-line treatment for febrile, hypoglycemic, or other metabolic seizures. Combination therapy may be necessary when tonic-clonic (grand mal) seizures coexist with absence seizures. /Phenytoin sodium anticonvulsants; not listed on the US product label/

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Drug Warnings
Leukopenia, neutropenia, agranulocytosis, thrombocytopenia, and pancytopenia have been reported. Eosinophilia, monocytosis, and leukocytosis have been reported. Simple anemia, hemolytic anemia, megaloblastic anemia, and aplastic anemia have been reported, but are uncommon.
Macropauses, measles-like rashes, scarlet fever-like rashes, urticaria-like rashes, purpuric rashes (associated with thrombocytopenia), and nonspecific rashes have been reported. Rare cases have been reported with exfoliative dermatitis, erythema multiforme (Stevens-Johnson syndrome), toxic epidermal neurolysis, and fatal dermatitis.
Skin pigmentation and rashes associated with lupus syndrome have been reported.
Drowsiness is dose-related and can be reduced by lowering the dose. Ataxia, diplopia, nystagmus, dysarthria, fatigue, irritability, choreiform movements, depression, and tremors have been reported. At the beginning of treatment, tension, nausea, vomiting, insomnia, and dizziness may occur. These symptoms are usually transient and tend to disappear with continued treatment. Increased levels of confusion, psychotic disorders, and seizures have been reported, but a clear causal relationship between these symptoms and the medication is not yet established.
Hepatitis, jaundice, and nephropathy have been reported, but a clear causal relationship between these adverse reactions and the drug has not been established. Hair loss, weight gain, edema, photophobia, and conjunctivitis have been reported. Polyarthropathy, pulmonary fibrosis, lupus syndrome, and Hodgkin's lymphoma-like lymphadenopathy have also been observed.
For more complete data on drug warnings for phenytoin (15 in total), please visit the HSDB record page.
Pharmacodynamics

Phenytoin is an antiepileptic drug used to treat epilepsy. Its primary site of action appears to be the motor cortex, where it inhibits the spread of seizures. Phenytoin may stabilize the neuronal threshold for overexcitation by promoting sodium efflux from neurons, preventing overexcitation caused by overstimulation or environmental changes (which can reduce the membrane sodium gradient). This includes reducing postsynaptic tonic enhancement. Loss of postsynaptic tonic enhancement prevents the spread of cortical epileptic foci to adjacent cortical areas. Mefenthromycin can reduce the maximum activity of the brainstem centers responsible for the tonic phase of tonic-clonic (grand mal) epilepsy.

C12H14N2O2

218.25

218.106

50-12-4

(R)-Mephenytoin;71140-51-7;(S)-Mephenytoin;70989-04-7;Mephenytoin-d5;1185032-66-9;Mephenytoin-d8

4060

White to off-white solid powder

1.154g/cm3

135-138ºC

1.74

1

2

2

16

310

0

CC[C@]1(C(=O)N(C(=O)N1)C)C2=CC=CC=C2

GMHKMTDVRCWUDX-UHFFFAOYSA-N

InChI=1S/C12H14N2O2/c1-3-12(9-7-5-4-6-8-9)10(15)14(2)11(16)13-12/h4-8H,3H2,1-2H3,(H,13,16)

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

Mephenytoin Methoin Mesantoin Phenantoin Methylphenetoin Insulton.

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)

DMSO : ~50 mg/mL (~229.10 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (11.45 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (11.45 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (11.45 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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