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 from the GI tract. Following oral administration, the drug has an onset of action of 30 minutes and a duration of action of 24-48 hours. Plasma concentrations required for therapeutic effects are not known; however, total serum concentrations of mephenytoin and its major metabolite of 25-40 ug/mL are reportedly associated with good seizure control without clinical intoxication.
Therapeutic serum concentrations range from 25 to 40 ug/mL (115 to 183 umol/L) for mephenytoin in combination with nirvanol /SRP: its active metabolite/. Time to peak concentration ranges from 45 minutes to 4 hours for mephenytoin and from 16 to 36 hours for nirvanol.
... /A/ single-dose study of mephenytoin (Mesantoin) ... was performed in adult inpatients on stable regimens of other anticonvulsants. Five patients received mephenytoin, 7 mg per kilogram of body weight. Serial blood sampling was performed rigorously. The time to peak concentration (Tmax) for mephenytoin was 1 hour, with a half-life (T 1/2) of 7 hours; the T 1/2 of its metabolite, 5-ethyl-5-phenylhydantion, was 96 hours. ... Saliva accurately represented the unbound fraction for /both/ agents. Mean salivary levels (as percentage of total levels) were 61% for mephenytoin, 73% for its metabolite ... . The implications for therapy are that following mephenytoin administration, the metabolite 5-ethyl-5-phenylhydantoin will provide anticonvulsant effectiveness, with its long half-life producing stable blood levels on simple dose schedules.

---

Metabolism / 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. ... Mephenytoin has an active metabolite, nirvanol (5-ethyl-5-phenylhydantoin). /Hydantoin anticonvulsants/
Mephenytoin is N-demethylated by the liver to form a highly toxic compound, 5,5-ethylphenylhydantoin. It is probably that this metabolite at least partly accounts for both the therapeutic and toxic effects of mephenytoin. The N-demethylated /metabolite/ may be excreted in the urine or further metabolized via p-hydroxylation of the phenyl group, conjugated with glucuronic acid, and excreted in the urine.
Human liver was used in investigations of mephenytoin p-hydroxylase, the enzyme presumably responsible for the genetic polymorphism in mephenytoin metabolism. A gas chromatographic assay method was developed to measure p-hydroxylation and N-demethylation which is the other major metabolic pathway. Both reactions were localized in the microsomal fraction and required NADPH. Inhibition of p-hydroxylation by CO, SKF 525-A, and metyrapone was demonstrated. It was concluded that a form of cytochrome P-450 catalyzes the reaction. The velocity of N-demethylation in human liver did not show saturation even at 500 microM substrate concentration. The p-hydroxylation, however, followed Michaelis-Menten kinetics. The Km, determined in five different livers, ranged from 59 to 143 microM. The linearity in Eadie-Hofstee plots was consistent with the involvement of a single catalytic site.
A major metabolite of the antiepileptic drug mephenytoin (3-methyl-5-ethyl-5-phenylhydantoin) has been identified in urine after a single oral dose of 100 mg of mephenytoin in man. Using chemical synthesis, gas chromatography-mass spectrometry, and nuclear magnetic resonance spectroscopy, /investigators/ established its chemical structure as 3-methyl-5-ethyl-5-(4-hydroxyphenyl)hydantoin (4-OH-M) which is a product of aromatic hydroxylation of mephenytoin in man. Quantitative determinations of 4-OH-M in urine of 10 volunteers showed that 43 +/- 7% (SD) of a single oral dose of 100 mg of mephenytoin were eliminated as the glucuronide of this metabolite. Urinary elimination of the demethylated metabolite, 5-ethyl-5-phenylhydantoin (Nirvanol), was low (1% of the dose per 24 hr) emphasizing the importance of 4-OH-M as the major metabolite after a single oral dose of mephenytoin. Other products of mephenytoin hydroxylation (2-OH-M, E-OH-M, or aliphatically hydroxylated 2-OH-ethyl-M) were not detectable under the conditions selected (less than 1 umol/24 hr).
For more Metabolism/Metabolites (Complete) data for MEPHENYTOIN (6 total), please visit the HSDB record page.

---

Biological Half-Life
Approximately 7 hours
... /A/ single-dose study of mephenytoin (Mesantoin) ... was performed in adult inpatients on stable regimens of other anticonvulsants. ... The time to peak concentration (Tmax) for mephenytoin was 1 hour, with a half-life (T 1/2) of 7 hours; the T 1/2 of its metabolite, 5-ethyl-5-phenylhydantion, was 96 hours. ...
About 7 hours, but for active metabolite, nirvanol, about 95 to 144 hours.

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. Dosage adjustments of the anticonvulsant may be necessary. In addition, the anticoagulant effect of coumarin- or indandione-derivative anticoagulants may be increased initially, but decrease with continued concurrent use. /Hydantoin anticonvulsants/
For more Interactions (Complete) data for MEPHENYTOIN (23 total), please visit the HSDB record page.

---

Non-Human Toxicity Values
LD50 Guinea pig oral 380 mg/kg
LD50 Rabbit oral 430 mg/kg
LD50 Cat 190 mg/kg
LD50 Mouse ip 317 mg/kg
For more Non-Human Toxicity Values (Complete) data for MEPHENYTOIN (7 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) in which the imidazolidine nucleus carries a methyl group at N-3 and has ethyl and phenyl substituents at C-5. An anticonvulsant, it is no longer available in the USA or the UK but is still studied largely because of its interesting hydroxylation polymorphism. It has a role as an anticonvulsant.
Mephenytoin is used for the treatment of refractory partial epilepsy. Mephenytoin is a solid. This compound belongs to the phenylhydantoins. These are heterocyclic aromatic compounds containing an imiazolidinedione moiety substituted by a phenyl group. Mephenytoin is known to target sodium channel protein type 5 subunit alpha. 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-derivative anticonvulsant used to control various partial seizures. Mephenytoin and oxazolidinedione derivatives are associated with higher incidences of blood dyscrasias compared to other anticonvulsants.
Mephenytoin is an Anti-epileptic Agent. The physiologic effect of mephenytoin is by means of Decreased Central Nervous System Disorganized Electrical Activity.
Mephenytoin is a heterocyclic organic compound with anticonvulsant property. Although the mechanism of action is not well established, mephenytoin potentially promotes sodium efflux from neurons in motor cortex, and stabilizes the threshold against hyperexcitability caused by excessive stimulation. Thus this agent reduces the membrane sodium gradient and prevents cortical seizure signal spreading. It may cause blood dyscrasias, therefore, this agent was only used after other less toxic anticonvulsants had failed.
An anticonvulsant effective in tonic-clonic epilepsy (EPILEPSY, TONIC-CLONIC). It may cause blood dyscrasias.

---

Drug Indication
For the treatment of refractory partial epilepsy.

---

Mechanism of Action
The mechanism of action of mephenytoin is not definitely known, but extensive research strongly suggests that its main mechanism is to block frequency-, use- and voltage-dependent neuronal sodium channels, and therefore limit repetitive firing of action potentials.
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 assoc with an increased cerebellar Purkinje cell discharge. /Hydantoin anticonvulsants/

---

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. ... Mephenytoin is also used in the treatment of simple partial (focal and Jacksonian) seizures in patients who have not responded to less 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 the US product label/

---

Drug Warnings
Leukopenia, neutropenia, agranulocytosis, thrombocytopenia, and pancytopenia have occurred. Eosinophilia, monocytosis, and leukocytosis have been described. Simple anemia, hemolytic anemia, megaloblastic anemia, and aplastic anemia have occurred but are uncommon.
Maculopapular, morbilliform, scarlatiniform, urticarial, purpuric (associated with thrombocytopenia), and nonspecific skin rashes have been reported. Exfoliative dermatitis, erythema multiform (Stevens-Johnson syndrome), and toxic epidermal neurolysis and fatal dermatitides have been described on rare occaisions. Skin pigmentation and rashes associated with a lupus erythematosis syndrome have also been reported.
Drowsiness is dose-related and may be reduced by a reduction in dose. Ataxia, diplopia, nystagmus, dysarthria, fatigue, irritability, choreiform movements, depression, and tremor have been encountered. Nervousness, nausea, vomiting, insomnia, and dizziness may occur during the initial stages of therapy. Generally, these symptoms are transient, often disappearing with continued treatment. Mental confusion and psychotic disturbances and increased seizures have been reported but a definite causal relationship with the drug is uncertain.
Hepatitis, jaundice, and nephrosis have been reported but a definite cause and effect relationship between the drug and these effects has not been established. Alopecia, weight gain, edema, photophobia, and conjunctivitis have been encountered. Polyarthropathy, pulmonary fibrosis, lupus erythematosis syndrome, and lymphadenopathy which simulates Hodgkin's disease have also been observed.
For more Drug Warnings (Complete) data for MEPHENYTOIN (15 total), please visit the HSDB record page.

---

Pharmacodynamics
Mephenytoin is an antiepileptic drug which can be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, mephenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Mephenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonic-clonic (grand mal) seizures.

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

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.

---

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.

---

View More

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.

---

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