Absorption, Distribution and Excretion
Methsuximide is absorbed from the GI tract and peak plasma concentrations are achieved in 1-3 hours. In one study, mean peak serum concentrations were 3 ug/mL following a single 600-mg dose and 6-7 ug/mL following a single 1.2-g dose of methsuximide.
Methsuximide is rapidly absorbed & metabolized. It is not bound significantly to plasma proteins.
Methsuximide is rapidly distributed throughout body after.../oral/ doses to rats, &.../it/ freely crosses blood-brain barrier.
Succinimide anticonvulsants are freely distributed to all body tissues, except fat.
For more Absorption, Distribution and Excretion (Complete) data for METHSUXIMIDE (7 total), please visit the HSDB record page.

---

Metabolism / Metabolites
Limited studies in patients who have taken extremely high doses of methsuximide and one study involving a small number of patients receiving methsuximide for the management of epilepsy indicate that the drug is metabolized via N-demethylation to N-demethylmethsuximide (NDM). Profound CNS depression following methsuximide overdosage has been attributed to this metabolite, and it is probable that the anticonvulsant effects of the drug result from NDM. Overdosage of methsuccimide may follow a biphasic course; patients have awakened and relapsed into coma within 24 hours. In one study in patients receiving methsuximide chronically, the plasma concentration of NDM was 700 times greater than the simultaneous plasma concentration of methsuximide. On the basis of this one study, a tentative therapeutic plasma NDM concentration of 10-40 ug/mL has been proposed; plasma NDM concentrations exceeding 40 ug/mL have been associated with toxicity and coma has been reported at plasma NDM concentrations of 150 ug/mL.
The pharmacokinetics of methsuximide and its major metabolite 2-methyl-2-phenylsuccinimide were studied in dogs after single intravenous doses. Plasma methsuximide levels were described by a two-compartment open model, and those of the metabolite were described by a one-compartment open model. An expression was derived that describes both methsuximide and metabolite plasma levels after methsuximide administration. Excellent fits were obtained between observed data and those predicted from the model. The metabolite, 2-methyl-2-phenylsuccinimide accounted for 40% of the overall elimination of methsuximide, and the half-life of the metabolite (15 hr) was much greater than that of the parent drug (1-3.5 hr). The results suggest that pharmacological effects after methsuximide administration may be due primarily to the metabolite, which may accumulate in the body during repeated doses.
Metabolism by hepatic microsomal enzymes in dog yields n-demethyl & parahydroxyphenyl derivatives & their glucuronides. ...
Following oral admin of 1-2 g methsuximide to dogs, alpha-(p-hydroxyphenyl)-alpha-methylsuccinimide & n-methyl-alpha-(p-hydroxyphenyl)-alpha-methylsuccinimide isolated from 48 hr urine as major metab & alpha-methyl-alpha-phenylsuccinimide as minor. No parent drug found.
Metab, n-desmethylmethsuximide level higher in phensuximide than methsuximide treated patients. Plasma elimination was 32 & 1-2 hr.

Half Life: 1.4-2.6 hours for mesuximide and 28-38 hours for the active metabolite.

---

Biological Half-Life
1.4-2.6 hours for mesuximide and 28-38 hours for the active metabolite.
The plasma half-life of methsuximide is slightly less than 3 hours.
The clinical efficacy of ... methsuximide was studied in relation to plasma concentrations of this compound and its desmethyl metabolite. Single- and chronic-dose studies of /methsuximide/ were carried out in five patients with intractable seizures. Patients were evaluated before and during treatment by 6-hour simultaneous video and telemetered electroencephalographic recordings to characterize the seizure type and by daily determinations of plasma antiepileptic drug concentrations. ... Methsuximide had a short half-life, averaging 1.4 hours, but its desmethyl metabolite had a mean half-life of 38 hours and therefore accumulated to levels in excess of 40 micrograms per milliliter. ...
Methsuximide ... was administered for 8 wk to 26 patients with complex partial seizures refractory to phenytoin and carbamazepine and phenobarbital or primidone. A 50% or greater reduction of complex partial seizure frequency was obtained in 8 patients. ... N-desmethylmethsuximide was the principle /metabolite/ detected in plasma and had the following pharmacokinetic values: accumulation half life, 49.7 hr; time to steady state, 10.4 days; elimination half life, 72.2 hr. ...

Toxicity Summary
Methsuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness which is common in absence (petit mal) seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli.

---

Hepatotoxicity
Prospective studies suggest that chronic methsuximide therapy is not accompanied by significant elevations in serum aminotransferase levels, although it has been shown to have hepatotoxicity in animals. Clinically apparent hepatotoxicity from methsuximide has not been reported, although hypersensitivity reactions with fever and rash are not uncommon (1% to 5%). The product label for methsuximide warns of hepatic dysfunction and recommends periodic liver function studies. Nevertheless, clinically apparent liver injury from methsuximide must be very rare, if it occurs at all.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).

---

Interactions
Concurrent use /with alcohol; central nervous system depression-producing medications; tricyclic antidepressants; loxapine; maprotiline; molindone; monoamine oxidase inhibitors; phenothiazines; pimozide; thioxanthenes/ may lower the convulsive threshold, enhance CNS depression, and decrease the effects of the anticonvulsant medication. /Succinimide anticonvulsants/
Requirements for folic acid may be increased in patients receiving anticonvulsant therapy. /Succinimide anticonvulsants/
Induction of hepatic microsomal enzyme activity resulting in increased metabolism and decreased serum concentrations and elimination half-lives of succinimide anticonvulsants and/or these medications /carbamazepine, phenobarbital, phenytoin, primidone/ may occur during concurrent therapy; monitoring of serum concentrations as a guide to dosage is recommended, especially when any anticonvulsant is added to or withdrawn from an existing regimen. /Succinimide anticonvulsants/
Concurrent use /with haloperidol/ may cause a change in the pattern and/or the frequency of epileptiform seizures; dosage adjustments of the anticonvulsant may be necessary; serum concentrations of haloperidol may be significantly reduced. /Succinimide anticonvulsants/
For more Interactions (Complete) data for METHSUXIMIDE (9 total), please visit the HSDB record page.

---

Non-Human Toxicity Values
LD50 Mouse oral 900 mg/kg

Therapeutic Uses
Anticonvulsants
Methsuximide is indicated for the management of absence seizures refractory to other medication. /Included in US product label/
Methsuximide may be used in the treatment of complex partial seizures (epilepsy). /Not included in US product label/
The use of methsuximide to control seizures in 25 children (mean age, 10.2 yr) with intractable epilepsy who were given methsuximide at a mean dose of 20.4 mg/kg/day in addition to their regular antiepileptic drug /therapy was examined/. Results showed that in 15 patients the drug was well tolerated and resulted in a 50% or greater reduction in seizure frequency. No serious or irreversible adverse effects were seen. Methsuximide is frequently overlooked and may be an effective adjunctive antiepileptic for children with intractable seizures.
Methsuximide was administered for 8 weeks to 26 patients with complex partial seizures (CPS) refractory to phenytoin and carbamazepine and phenobarbital or primidone. A 50% or greater reduction in CPS frequency was obtained in eight patients. MSM therapy was continued chronically in these eight patients, and five continued to have a 50% or greater reduction in CPS frequency after 3 to 34 months of follow-up. ...

---

Drug Warnings
The blood dyscrasia-causing effects of succinimide anticonvulsants may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks. /Succinimide anticonvulsants/
Adverse GI effects occur frequently during methsuximide therapy and include nausea or vomiting, weight loss, anorexia, epigastric or abdominal pain, diarrhea, and constipation.
Adverse nervous system effects of methsuximide include drowsiness, ataxia, dizziness, irritability and nervousness, headache, photophobia, blurred vision, hiccups, and insomnia. The most common adverse nervous system effects are drowsiness, ataxia, and dizziness. Adverse psychologic effects have included instability, hypochondriacal behavior, aggressiveness, and mental confusion, depression, and slowness. Rarely, psychosis, suicidal behavior, and auditory hallucinations have been reported.
Adverse hematologic effects associated with methsuximide include eosinophilia, leukopenia, monocytosis, and pancytopenia. Adverse dermatologic effects may include urticaria, pruritic erythematous rash, and Steven-Johnson syndrome. Adverse genitourinary effects associated with methsuximide include proteinuria and microscopic hematuria. Periorbital edema and hyperemia have also occurred. Systemic lupus erythematosus has been associated with succinimide use.
For more Drug Warnings (Complete) data for METHSUXIMIDE (9 total), please visit the HSDB record page.

---

Pharmacodynamics
Used in the treatment of epilepsy. Methsuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness which is common in absence (petit mal) seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli.

C12H13NO2

203.24

203.095

77-41-8

6476

Crystals from dilute alcohol
White to grayish white, crystalline powder

1.59g/cm3

489.2ºC at 760 mmHg

52-53°

191.7ºC

1.692

1.27

0

2

1

15

294

0

CC1(CC(=O)N(C)C1=O)C2=CC=CC=C2

AJXPJJZHWIXJCJ-UHFFFAOYSA-N

InChI=1S/C12H13NO2/c1-12(9-6-4-3-5-7-9)8-10(14)13(2)11(12)15/h3-7H,8H2,1-2H3

1,3-dimethyl-3-phenylpyrrolidine-2,5-dione

Celontin; Mesuximide; Methsuximide

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

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.

---

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).

View More

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)

---

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).

View More

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

---

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.

---

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