怀孕期间，美芬妥英（药物，100 mg/kg、200 mg/kg）在 200 mg/kg 剂量下可降低母亲体重增加，并增加后代杂交，但在 100 mg/kg 剂量下则无此作用。 Sprague-Dawley CD Mefentoin 可显着降低小鼠的血液胆固醇和甘油三酯水平，并且当连续 16 天腹腔内注射 20 mg/kg 剂量时，可能会产生降血脂作用 [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.

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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.

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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.

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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.

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Drug Indication
For the treatment of refractory partial epilepsy.

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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/

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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. ... 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/

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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.

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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

49.41

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (11.45 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (11.45 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (11.45 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。