Mephenytoin

218.25

218.25

200-012-8

34652

DTXSID9023257

off-white

N - Nervous system

2933210000

49.41000

1.74020

off-white solid

1.154±0.06 g/cm3 (20 ºC 760 Torr)

135-138 °C

358.94°C (rough estimate)

1.6660 (estimate)

9.70e-01 g/L

2-8°C

3.8X10-8 mm Hg at 25 deg C (est)

LD50 i.p. in mice: 300 mg/kg (Dzhagatspanyan)

pKa 8.1 (Uncertain)

Henry's Law constant = 4.90X10-10 atm-cu m/mol at 25 °C (est)

8.51|pKa = 8.51 at 20 to 25 °C

Forms a water-soluble sodium salt which has an alkaline reaction.|Hydroxyl radical reaction rate constant = 1.07X10-11 cu cm/molec-sec at 25 °C (est)

2-8°C

NONH for all modes of transport

2

Xn

26-36

Xn

P301 + P312 + P330-P305 + P351 + P338

22-36/37/38

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies discontinued drug products. Mephenytoin is included on this list.

Strasnick B, Jacobson JT; J Am Acad Audiol 6 (1): 28-38 (1995). Teratogenic hearing loss /is reviewed/.|Maternal factors, medications and drug exposure in congenital limb reduction defects.[Foster UG, Baird PA; Environ Health Perspect 101 (Suppl 3): 269-74 (1993)]|Markova IV; Farmakol Toksikol 53 (4): 82-6 (1990). The undesirable action of drugs on the embryo, fetus and newborn infant.|Mattison DR, et al; Perinatal Pharmacol 13-41 (1989). Effects of drugs and chemicals on the fetus.|For more Special Reports (Complete) data for MEPHENYTOIN (8 total), please visit the HSDB record page.

|Warning|H302 (97.62%): Harmful if swallowed [Warning Acute toxicity, oral]|P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P340, P305+P351+P338, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 42 companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

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.

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.

Because acute attacks of porphyria may be precipitated by anticonvulsants, a therapeutic dilemma arises when seizures complicate hepatic porphyria. The list of unsafe agents includes barbiturates, primidone, phenytoin, mephenytoin, ethotoin, ethosuximide, methsuximide, phensuximide, and trimethadione. ...|The urinary metabolic profile of mephenytoin and its oxidative metabolites indicates significant stereoselective metabolism of its two enantiomers. Also, polymorphic oxidation, which is present in about 2 to 5% of the Caucasian population, has been demonstrated by an impaired ability to 4-hydroxylate this anticonvulsant. In order to determine the consequences of such metabolism, the plasma concentration/time profiles of the enantiomers of mephenytoin and its N-demethylated metabolite, phenylethylhydantoin (PEH), were investigated after a single p.o. dose of racemic mephenytoin in normal subjects with different metabolizing ability for mephenytoin [extensive metabolizer (EM) vs. poor metabolizer (PM) phenotypes]. In the EM subjects, the disposition of S- and R-mephenytoin was markedly different with a 100- to 200-fold difference in mean oral clearance (4.7 vs. 0.027 liters/min) and a 30- to 40-fold difference in elimination half-life (2.1 vs. 76 hr). In these same subjects, R-PEH concentrations significantly accumulated over several days and then very slowly declined with an apparent half-life of about 200 hr. Plasma levels of S-PEH were essentially negligible. In contrast, the stereoselective elimination of mephenytoin was reduced markedly in subjects of the PM phenotype, with the disposition of the S-enantiomer being the same as that for R-mephenytoin, which in turn was similar to that observed for this enantiomer in EMs. Almost comparable plasma levels of S- and R-PEH were also present in PMs. Only a small amount (less than 5%) of unchanged mephenytoin was excreted in the urine regardless of phenotype.|Following equal doses of phenytoin, total plasma phenytoin concentrations are lower in chronic uremic patients than in non-uremic patients which suggests an altered metabolic disposition of the drug in patients with uremia. /Phenytoin/

While data specific to mephenytoin were not located(SRC, 2007), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

For the treatment of refractory partial epilepsy.

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/

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.

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.

Drugs used to prevent SEIZURES or reduce their severity. (See all compounds classified as Anticonvulsants.)

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.

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.

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.

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/

Since there is no specific antidote for overdose with hydantoin anticonvulsants, treatment is symptomatic and supportive and may include the following: ... Multiple oral doses of charcoal and cathartic may shorten the duration of symptoms. Supportive care - oxygen, vasopressors, and assisted ventilation may be necessary for CNS, respiratory, or cardiovascular depression. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation. Following recovery, careful evaluation of blood-forming organs is advisable. /Hydantoin anticonvulsants/|Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen. Treat stupor and coma if they occur. Protect the patient from self-injury caused by ataxia. If seizures occur, consider an alternate diagnosis and treat with other usual anticonvulsants. If hypotension occurs with intravenous phenytoin administration, immediately stop the infusion and administer intravenous fluids and pressors if necessary. There are no specific antidotes. Decontamination: administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. Elimination: Repeat-dose activated charcoal may enhance phenytoin elimination but is not necessary and may increase the risk of aspiration pneumonitis in drowsy patients. There is no role for diuresis, dialysis, or hemoperfusion.|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ /Investigators/ tested the ability of 194 unrelated, healthy Jordanian volunteers to metabolize S-mephenytoin. Mephenytoin (100 mg) was coadministered with debrisoquin (10 mg) orally and urine was collected for 8 hours. Mephenytoin metabolism was tested according to three measures: the amount of 4-hydroxymephenytoin, the S/R enantiomeric ratio, and the presence of a polar, acid-labile metabolite in urine collected for 8 hours after the dose. The S/R ratio and the presence of the acid-labile metabolite were determined in the urine of 16 patients who had low amounts of 4-hydroxymephenytoin (log hydroxylation index > or = 1). On examination of these three parameters of oxidation status, nine subjects were found to be poor metabolizers of mephenytoin by all three parameters. Thus 4.6% (95% confidence interval of 1.6% to 7.6%) of Jordanian subjects studied were poor metabolizers of mephenytoin. According to the Hardy-Weinberg Law, the frequency of the recessive autosomal gene controlling the poor metabolizer status of mephenytoin was predicted to be 0.215% (95% confidence interval of 0.146% to 0.283%). These results are on the same order of magnitude as those determined in European white populations and constitute the first report in Arab populations.|/SIGNS AND SYMPTOMS/ 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.|/SIGNS AND SYMPTOMS/ Clinical effects of overdose include ataxia (clumsiness or unsteadiness) or staggering walk, blurred or double vision, severe confusion, severe dizziness or drowsiness, dysarthria (stuttering) or slurred speech, hyperreflexia, nausea and vomiting, nystagmus (continuous, uncontrolled back-and-forth and/or rolling eye movements), tremor, and unusual tiredness or weakness. /Hydantoin anticonvulsants/|/CASE REPORTS/ ... A 26-year-old female overdosed on approximately 12 g of mephenytoin and an unknown amount of valproic acid. She became comatose, developing pulmonary aspiration and pancreatitis with fever. Her Intensive Care Unit treatment was prolonged with slow resolution over 10 days.|For more Human Toxicity Excerpts (Complete) data for MEPHENYTOIN (9 total), please visit the HSDB record page.

5 Ethyl 3 Methyl 5 Phenylhydantoin

METHOIN|SEDANTOINAL

Analyte: mephenytoin; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards|Analyte: mephenytoin; matrix: chemical identification; procedure: ultraviolet absorption spectrophotometry with comparison to standards|Analyte: mephenytoin; matrix: chemical purity; procedure: liquid chromatography with detection at 257 nm and comparison to standards|Analyte: mephenytoin; matrix: pharmaceutical preparation (tablet); procedure: liquid chromatography with detection at 257 nm and comparison to standards (chemical purity)

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