Identification

Name
Ethosuximide
Accession Number
DB00593  (APRD00318)
Type
Small Molecule
Groups
Approved
Description

An anticonvulsant especially useful in the treatment of absence seizures unaccompanied by other types of seizures. [PubChem]

Structure
Thumb
Synonyms
  • (+-)-2-Ethyl-2-methylsuccinimide
  • (±)-2-ethyl-2-methylsuccinimide
  • 2-ethyl-2-methylsuccinimide
  • 2-Methyl-2-ethylsuccinimide
  • 3-ethyl-3-methyl-2,5-pyrrolidinedione
  • 3-Ethyl-3-methylsuccinimide
  • 3-Methyl-3-ethylpyrrolidine-2,5-dione
  • 3-Methyl-3-ethylsuccinimide
  • Aethosuximide
  • alpha-Ethyl-alpha-methylsuccinimide
  • alpha-Methyl-alpha-ethylsuccinimide
  • Atysmal
  • Ethosuximid
  • Ethosuximide
  • Ethosuximidum
  • Etosuximida
  • gamma-Ethyl-gamma-methyl-succinimide
  • gamma-Methyl-gamma-ethyl-succinimide
  • Thilopemal
  • γ-ethyl-γ-methyl-succinimide
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ZarontinCapsule250 mg/1OralParke Davis Div Of Pfizer Inc2000-09-22Not applicableUs
Zarontin Cap 250mgCapsule250 mgOralErfa Canada 2012 Inc1960-12-31Not applicableCanada
Zarontin Syr 250mg/5mlSyrup250 mgOralErfa Canada 2012 Inc1964-12-31Not applicableCanada
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
EthosuximideSolution250 mg/5mLOralVersa Pharm Incorporated2004-01-01Not applicableUs
EthosuximideSolution250 mg/5mLOralTeva Pharmaceuticals USA, Inc.1994-07-01Not applicableUs
EthosuximideCapsule250 1/1OralZydus Pharmaceuticals Usa, Inc.2012-10-10Not applicableUs
EthosuximideCapsule250 mg/1OralGreenstone, Llc2000-09-22Not applicableUs
EthosuximideCapsule250 mg/1OralHeritage2012-10-10Not applicableUs
EthosuximideCapsule250 mg/1OralAvera McKennan Hospital2015-10-30Not applicableUs69189 040020180907 15195 1czugf3
EthosuximideSolution250 mg/5mLOralMikart, Inc.2003-12-22Not applicableUs
EthosuximideCapsule250 mg/1OralTeva2002-11-012017-04-30Us50111 0901 01 nlmimage10 8b3245d2
EthosuximideCapsule, liquid filled250 mg/1OralBanner Life Sciences Llc.2015-06-01Not applicableUs
EthosuximideCapsule250 mg/1OralVersa Pharm Incorporated2008-09-01Not applicableUs61748 0025 01 nlmimage10 8c3bc63e
International/Other Brands
Emeside (Chemidex) / Ethymal (Apotex Europe) / Etoxin (Apsen) / Petimid (Osel) / Petinimid (Gerot) / Petnidan (Desitin) / Suxilep (Jenapharm) / Suxinutin (McNeil) / Zarondan (Pfizer)
Categories
UNII
5SEH9X1D1D
CAS number
77-67-8
Weight
Average: 141.1677
Monoisotopic: 141.078978601
Chemical Formula
C7H11NO2
InChI Key
HAPOVYFOVVWLRS-UHFFFAOYSA-N
InChI
InChI=1S/C7H11NO2/c1-3-7(2)4-5(9)8-6(7)10/h3-4H2,1-2H3,(H,8,9,10)
IUPAC Name
3-ethyl-3-methylpyrrolidine-2,5-dione
SMILES
CCC1(C)CC(=O)NC1=O

Pharmacology

Indication

For the treatment of petit mal epilepsy.

Associated Conditions
Pharmacodynamics

Used in the treatment of epilepsy. Ethosuximide 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.

Mechanism of action

Binds to T-type voltage sensitive calcium channels. Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1G gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by mibefradil. A particularity of this type of channels is an opening at quite negative potentials and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes.

TargetActionsOrganism
AVoltage-dependent T-type calcium channel subunit alpha-1G
inhibitor
Human
Absorption

Bioavailability following oral administration is 93%.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Hepatic, via CYP3A4 and CYP2E1.

Route of elimination
Not Available
Half life

53 hours

Clearance
Not Available
Toxicity

Acute overdoses may produce nausea, vomiting, and CNS depression including coma with respiratory depression.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Ethosuximide can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of Ethosuximide can be decreased when combined with (S)-Warfarin.
16-BromoepiandrosteroneThe metabolism of Ethosuximide can be decreased when combined with 16-Bromoepiandrosterone.
2,5-Dimethoxy-4-ethylamphetamine2,5-Dimethoxy-4-ethylamphetamine can cause a decrease in the absorption of Ethosuximide resulting in a reduced serum concentration and potentially a decrease in efficacy.
2,5-Dimethoxy-4-ethylthioamphetamine2,5-Dimethoxy-4-ethylthioamphetamine can cause a decrease in the absorption of Ethosuximide resulting in a reduced serum concentration and potentially a decrease in efficacy.
3-isobutyl-1-methyl-7H-xanthineEthosuximide may increase the excretion rate of 3-isobutyl-1-methyl-7H-xanthine which could result in a lower serum level and potentially a reduction in efficacy.
3,4-Methylenedioxyamphetamine3,4-Methylenedioxyamphetamine can cause a decrease in the absorption of Ethosuximide resulting in a reduced serum concentration and potentially a decrease in efficacy.
3,5-diiodothyropropionic acidThe metabolism of Ethosuximide can be decreased when combined with 3,5-diiodothyropropionic acid.
4-Bromo-2,5-dimethoxyamphetamine4-Bromo-2,5-dimethoxyamphetamine can cause a decrease in the absorption of Ethosuximide resulting in a reduced serum concentration and potentially a decrease in efficacy.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Ethosuximide.
Food Interactions
  • Avoid alcohol.
  • Take with food.

References

Synthesis Reference

Miller, C.A. and Long, L.M.; U.S. Patent 2,993,835; July 25,1961; assigned to Parke, Davis and Company.

General References
  1. Patsalos PN: Properties of antiepileptic drugs in the treatment of idiopathic generalized epilepsies. Epilepsia. 2005;46 Suppl 9:140-8. [PubMed:16302888]
  2. Coulter DA, Huguenard JR, Prince DA: Specific petit mal anticonvulsants reduce calcium currents in thalamic neurons. Neurosci Lett. 1989 Mar 13;98(1):74-8. [PubMed:2710401]
  3. Coulter DA, Huguenard JR, Prince DA: Characterization of ethosuximide reduction of low-threshold calcium current in thalamic neurons. Ann Neurol. 1989 Jun;25(6):582-93. [PubMed:2545161]
  4. Coulter DA, Huguenard JR, Prince DA: Differential effects of petit mal anticonvulsants and convulsants on thalamic neurones: calcium current reduction. Br J Pharmacol. 1990 Aug;100(4):800-6. [PubMed:2169941]
  5. Kostyuk PG, Molokanova EA, Pronchuk NF, Savchenko AN, Verkhratsky AN: Different action of ethosuximide on low- and high-threshold calcium currents in rat sensory neurons. Neuroscience. 1992 Dec;51(4):755-8. [PubMed:1336826]
External Links
Human Metabolome Database
HMDB0014731
KEGG Drug
D00539
KEGG Compound
C07505
PubChem Compound
3291
PubChem Substance
46507617
ChemSpider
3175
BindingDB
50240424
ChEBI
4887
ChEMBL
CHEMBL696
Therapeutic Targets Database
DAP000526
PharmGKB
PA449533
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Ethosuximide
ATC Codes
N03AD51 — Ethosuximide, combinationsN03AD01 — Ethosuximide
AHFS Codes
  • 28:12.20 — Succinimides
FDA label
Download (174 KB)
MSDS
Download (73.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2TerminatedPreventionMigrainous Headache1
2CompletedSupportive CareCancers / Peripheral Neuropathy1
2CompletedTreatmentNeuropathic Traumatic Pain / Pain NRS ≥ 41
2RecruitingTreatmentIrritable Bowel Syndrome (IBS)1
2TerminatedTreatmentComplex Regional Pain Syndromes (CRPS)1
3CompletedTreatmentChildhood Absence Epilepsy / Epilepsies / Petit Mal Epilepsy / Seizures1
4RecruitingTreatmentEpilepsies1

Pharmacoeconomics

Manufacturers
  • Banner pharmacaps inc
  • Convenant pharma inc
  • Parke davis div warner lambert co
  • Mikart inc
  • Pharmaceutical assoc inc div beach products
  • Teva pharmaceuticals usa
  • Parke davis pharmaceutical research div warner lambert co
Packagers
  • Barr Pharmaceuticals
  • Catalent Pharma Solutions
  • Mikart Inc.
  • Pfizer Inc.
  • Pharmaceutical Association
  • Pliva Inc.
  • Swiss Caps Ag
  • Teva Pharmaceutical Industries Ltd.
  • Versapharm Inc.
Dosage forms
FormRouteStrength
CapsuleOral250 mg/1
CapsuleOral250 1/1
Capsule, liquid filledOral250 mg/1
SolutionOral250 mg/5mL
CapsuleOral250 mg
SyrupOral250 mg
Prices
Unit descriptionCostUnit
Ethosuximide 250 mg/5ml Solution 474ml Bottle84.2USD bottle
Ethosuximide 250 mg capsule1.26USD capsule
Zarontin 250 mg capsule1.16USD capsule
Zarontin 250 mg/5ml Solution0.34USD ml
Zarontin 50 mg/ml Syrup0.07USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)64.5 °CPhysProp
water solubility39.2 g/LNot Available
logP0.38ATKINSON,HC & BERG,EJ (1988)
Predicted Properties
PropertyValueSource
Water Solubility101.0 mg/mLALOGPS
logP0.1ALOGPS
logP0.55ChemAxon
logS-0.15ALOGPS
pKa (Strongest Acidic)10.73ChemAxon
pKa (Strongest Basic)-6.6ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area46.17 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity35.96 m3·mol-1ChemAxon
Polarizability14.45 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9983
Caco-2 permeable+0.5262
P-glycoprotein substrateNon-substrate0.5832
P-glycoprotein inhibitor INon-inhibitor0.7859
P-glycoprotein inhibitor IINon-inhibitor0.9923
Renal organic cation transporterNon-inhibitor0.8867
CYP450 2C9 substrateNon-substrate0.8492
CYP450 2D6 substrateNon-substrate0.9115
CYP450 3A4 substrateSubstrate0.5108
CYP450 1A2 substrateNon-inhibitor0.9242
CYP450 2C9 inhibitorNon-inhibitor0.9072
CYP450 2D6 inhibitorNon-inhibitor0.9232
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.9276
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.93
Ames testNon AMES toxic0.858
CarcinogenicityNon-carcinogens0.8526
BiodegradationNot ready biodegradable0.9299
Rat acute toxicity1.9213 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9939
hERG inhibition (predictor II)Non-inhibitor0.9795
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (8.34 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - EI-BGC-MSsplash10-08mi-9400000000-44583cdc88d3203a4e84
GC-MS Spectrum - CI-BGC-MSsplash10-0006-1900000000-1c27ada66f7846f9d155
GC-MS Spectrum - CI-BGC-MSsplash10-0006-2900000000-19e57defe9ded4ed42b4
Mass Spectrum (Electron Ionization)MSsplash10-08mi-9300000000-3d87944377ee1f85803d
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as pyrrolidine-2-ones. These are pyrrolidines which bear a C=O group at position 2 of the pyrrolidine ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyrrolidines
Sub Class
Pyrrolidones
Direct Parent
Pyrrolidine-2-ones
Alternative Parents
N-unsubstituted carboxylic acid imides / Dicarboximides / Lactams / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
2-pyrrolidone / Carboxylic acid imide / Dicarboximide / Carboxylic acid imide, n-unsubstituted / Lactam / Carboxylic acid derivative / Azacycle / Carbonyl group / Organooxygen compound / Organonitrogen compound
Molecular Framework
Aliphatic heteromonocyclic compounds
External Descriptors
pyrrolidinone, dicarboximide (CHEBI:4887)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Scaffold protein binding
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1G
Uniprot ID
O43497
Uniprot Name
Voltage-dependent T-type calcium channel subunit alpha-1G
Molecular Weight
262468.62 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  2. Gomora JC, Daud AN, Weiergraber M, Perez-Reyes E: Block of cloned human T-type calcium channels by succinimide antiepileptic drugs. Mol Pharmacol. 2001 Nov;60(5):1121-32. [PubMed:11641441]
  3. Wang G, Thompson SM: Maladaptive homeostatic plasticity in a rodent model of central pain syndrome: thalamic hyperexcitability after spinothalamic tract lesions. J Neurosci. 2008 Nov 12;28(46):11959-69. doi: 10.1523/JNEUROSCI.3296-08.2008. [PubMed:19005061]
  4. Matthews EA, Dickenson AH: Effects of ethosuximide, a T-type Ca(2+) channel blocker, on dorsal horn neuronal responses in rats. Eur J Pharmacol. 2001 Mar;415(2-3):141-9. [PubMed:11274992]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Bachmann K, He Y, Sarver JG, Peng N: Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of ethosuximide by human hepatic microsomal enzymes. Xenobiotica. 2003 Mar;33(3):265-76. doi: 10.1080/0049825021000061606 . [PubMed:12637244]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Bachmann K, He Y, Sarver JG, Peng N: Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of ethosuximide by human hepatic microsomal enzymes. Xenobiotica. 2003 Mar;33(3):265-76. doi: 10.1080/0049825021000061606 . [PubMed:12637244]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Monooxygenase activity
Specific Function
Exhibits low testosterone 6-beta-hydroxylase activity.
Gene Name
CYP3A43
Uniprot ID
Q9HB55
Uniprot Name
Cytochrome P450 3A43
Molecular Weight
57669.21 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]

Drug created on June 13, 2005 07:24 / Updated on October 16, 2018 08:28