Identification

Name
Paramethadione
Accession Number
DB00617  (APRD00236)
Type
Small Molecule
Groups
Approved
Description

Paramethadione is an anticonvulsant in the oxazolidinedione class. It is associated with fetal trimethadione syndrome, which is also known as paramethadione syndrome.

Structure
Thumb
Synonyms
  • Parametadiona
  • Parametadione
  • Paramethadione
  • Paramethadionum
International/Other Brands
Paradione
Categories
UNII
Z615FRW64N
CAS number
115-67-3
Weight
Average: 157.1671
Monoisotopic: 157.073893223
Chemical Formula
C7H11NO3
InChI Key
VQASKUSHBVDKGU-UHFFFAOYSA-N
InChI
InChI=1S/C7H11NO3/c1-4-7(2)5(9)8(3)6(10)11-7/h4H2,1-3H3
IUPAC Name
5-ethyl-3,5-dimethyl-1,3-oxazolidine-2,4-dione
SMILES
CCC1(C)OC(=O)N(C)C1=O

Pharmacology

Indication

Used for the control of absence (petit mal) seizures that are refractory to treatment with other medications.

Pharmacodynamics

Paramethadione is an oxazolidinedione anticonvulsant similar to trimethadione that acts on the central nervous system (CNS) to reduce the number of absence seizures (often seen in epileptics). Absence seizures involve an interruption to consciousness where the person experiencing the seizure seems to become vacant and unresponsive for a short period of time (usually up to 30 seconds). Paramethadione acts on thalamic neurons in the thalamic reticular nucleus (which studies have shown to be associated with absence seizures, von Krosigk et al., 1993).

Mechanism of action

Dione anticonvulsants such as paramethadione reduce T-type calcium currents in thalamic neurons (including thalamic relay neurons). This inhibits corticothalamic transmission and raises the threshold for repetitive activity in the thalamus. This results in a dampening of the abnormal thalamocortical rhythmicity proposed to underlie the 3-Hz spike-and-wave discharge seen on electroencephalogram (EEG) during absence seizures.

TargetActionsOrganism
AVoltage-dependent T-type calcium channel subunit alpha-1I
suppressor
Human
Absorption

Rapid via the digestive tract.

Volume of distribution
Not Available
Protein binding

Not significant

Metabolism

Primarily hepatic (mainly via cytochrome P450 isozyme 2C9), paramethadione is completely demethylated to 5-ethyl-5-methyl-2,4-oxazolidinedione, the active metabolite.

Route of elimination
Not Available
Half life

12 to 24 hours (however the half-life for the active metabolite is not known)

Clearance
Not Available
Toxicity

Symptoms of overdose include clumsiness or unsteadiness, coma, severe dizziness, severe drowsiness, severe nausea, and problems with vision.

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

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Paramethadione.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Paramethadione.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Paramethadione is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3-isobutyl-1-methyl-7H-xanthineParamethadione 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-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when Paramethadione is combined with 3,4-Methylenedioxyamphetamine.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Paramethadione.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when Paramethadione is combined with 4-Bromo-2,5-dimethoxyamphetamine.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Paramethadione.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when Paramethadione is combined with 4-Methoxyamphetamine.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Paramethadione.
Food Interactions
Not Available

References

General References
  1. Hoffman DJ, Chun AH: Paramethadione and metabolite serum levels in humans after a single oral paramethadione dose. J Pharm Sci. 1975 Oct;64(10):1702-3. [PubMed:1185541]
  2. Feldman GL, Weaver DD, Lovrien EW: The fetal trimethadione syndrome: report of an additional family and further delineation of this syndrome. Am J Dis Child. 1977 Dec;131(12):1389-92. [PubMed:412416]
External Links
Human Metabolome Database
HMDB0014755
KEGG Drug
D00495
KEGG Compound
C07411
PubChem Compound
8280
PubChem Substance
46509173
ChemSpider
7979
ChEBI
7921
ChEMBL
CHEMBL1100
Therapeutic Targets Database
DAP001266
PharmGKB
PA164748880
Drugs.com
Drugs.com Drug Page
Wikipedia
Paramethadione
ATC Codes
N03AC01 — Paramethadione

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
  • Abbott laboratories pharmaceutical products div
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
boiling point (°C)101.5 °CNot Available
water solubility8.4 mg/mLNot Available
logP0.3Not Available
Predicted Properties
PropertyValueSource
Water Solubility135.0 mg/mLALOGPS
logP0.9ALOGPS
logP1.03ChemAxon
logS-0.07ALOGPS
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area46.61 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity37.72 m3·mol-1ChemAxon
Polarizability15.39 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9955
Blood Brain Barrier+0.9804
Caco-2 permeable+0.5334
P-glycoprotein substrateNon-substrate0.8117
P-glycoprotein inhibitor INon-inhibitor0.5232
P-glycoprotein inhibitor IINon-inhibitor0.5937
Renal organic cation transporterNon-inhibitor0.9572
CYP450 2C9 substrateNon-substrate0.8651
CYP450 2D6 substrateNon-substrate0.8869
CYP450 3A4 substrateSubstrate0.5517
CYP450 1A2 substrateNon-inhibitor0.8174
CYP450 2C9 inhibitorNon-inhibitor0.812
CYP450 2D6 inhibitorNon-inhibitor0.914
CYP450 2C19 inhibitorNon-inhibitor0.7845
CYP450 3A4 inhibitorNon-inhibitor0.8711
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8976
Ames testNon AMES toxic0.7081
CarcinogenicityNon-carcinogens0.8298
BiodegradationNot ready biodegradable0.8515
Rat acute toxicity2.2682 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9921
hERG inhibition (predictor II)Non-inhibitor0.9752
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (7.42 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - EI-BGC-MSsplash10-004i-6900000000-cb5c4b22a5f6eea03ccb
GC-MS Spectrum - CI-BGC-MSsplash10-0a4i-0900000000-6d7437f8325dda84507a
Mass Spectrum (Electron Ionization)MSsplash10-0006-9300000000-5b8273da08cb63d81fcf
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 oxazolidinediones. These are compounds containing an oxazolidine ring which bears two ketones.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Azolidines
Sub Class
Oxazolidines
Direct Parent
Oxazolidinediones
Alternative Parents
Dicarboximides / Carbamate esters / Organic carbonic acids and derivatives / Oxacyclic compounds / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Oxazolidinedione / Dicarboximide / Carbamic acid ester / Carbonic acid derivative / Oxacycle / Azacycle / Carboxylic acid derivative / Hydrocarbon derivative / Organopnictogen compound / Organic oxygen compound
Molecular Framework
Aliphatic heteromonocyclic compounds
External Descriptors
oxazolidinone (CHEBI:7921)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Suppressor
General Function
Voltage-gated calcium channel activity
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
CACNA1I
Uniprot ID
Q9P0X4
Uniprot Name
Voltage-dependent T-type calcium channel subunit alpha-1I
Molecular Weight
245100.8 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]

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. Kurata N, Nishimura Y, Iwase M, Fischer NE, Tang BK, Inaba T, Yasuhara H: Trimethadione metabolism by human liver cytochrome P450: evidence for the involvement of CYP2E1. Xenobiotica. 1998 Nov;28(11):1041-7. [PubMed:9879636]
  2. Tanaka E, Terada M, Misawa S: Cytochrome P450 2E1: its clinical and toxicological role. J Clin Pharm Ther. 2000 Jun;25(3):165-75. [PubMed:10886461]
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. Tanaka E, Kurata N, Yasuhara H: Involvement of cytochrome P450 2C9, 2E1 and 3A4 in trimethadione N-demethylation in human microsomes. J Clin Pharm Ther. 2003 Dec;28(6):493-6. [PubMed:14651673]
  2. Kurata N, Nishimura Y, Iwase M, Fischer NE, Tang BK, Inaba T, Yasuhara H: Trimethadione metabolism by human liver cytochrome P450: evidence for the involvement of CYP2E1. Xenobiotica. 1998 Nov;28(11):1041-7. [PubMed:9879636]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Curator comments
This enzyme effect is supported only by 1 in vitro study.
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Tanaka E, Kurata N, Yasuhara H: Involvement of cytochrome P450 2C9, 2E1 and 3A4 in trimethadione N-demethylation in human microsomes. J Clin Pharm Ther. 2003 Dec;28(6):493-6. [PubMed:14651673]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Kurata N, Nishimura Y, Iwase M, Fischer NE, Tang BK, Inaba T, Yasuhara H: Trimethadione metabolism by human liver cytochrome P450: evidence for the involvement of CYP2E1. Xenobiotica. 1998 Nov;28(11):1041-7. [PubMed:9879636]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 04:47