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Identification
NameTrimethadione
Accession NumberDB00347  (APRD00315)
TypeSmall Molecule
GroupsApproved
Description

An anticonvulsant effective in absence seizures, but generally reserved for refractory cases because of its toxicity. (From AMA Drug Evaluations Annual, 1994, p378)

Structure
Thumb
Synonyms
SynonymLanguageCode
TridioneNot AvailableNot Available
TrimethadionNot AvailablePh. Eur. 7
TriméthadioneNot AvailableDCF
TrimethadionumNot AvailablePh. Eur. 7, Ph. Int. 4
TrimethinumNot AvailableIS
TroxidoneNot AvailableIS
SaltsNot Available
Brand names
NameCompany
MinoaleDainippon Sumitomo
TridioneAbbott
Brand mixturesNot Available
Categories
CAS number127-48-0
WeightAverage: 143.1406
Monoisotopic: 143.058243159
Chemical FormulaC6H9NO3
InChI KeyIRYJRGCIQBGHIV-UHFFFAOYSA-N
InChI
InChI=1S/C6H9NO3/c1-6(2)4(8)7(3)5(9)10-6/h1-3H3
IUPAC Name
trimethyl-1,3-oxazolidine-2,4-dione
SMILES
CN1C(=O)OC(C)(C)C1=O
Mass Specshow(7.69 KB)
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassAzolidines
SubclassOxazolidines
Direct parentOxazolidinediones
Alternative parentsN-substituted Carboxylic Acid Imides; Tertiary Carboxylic Acid Amides; Tertiary Amines; Carbamic Acids and Derivatives; Carboxylic Acids; Polyamines
Substituentscarboxylic acid imide, n-substituted; tertiary carboxylic acid amide; carbamic acid derivative; carboxamide group; tertiary amine; polyamine; carboxylic acid derivative; carboxylic acid; amine; organonitrogen compound
Classification descriptionThis compound belongs to the oxazolidinediones. These are compound containing an oxazolidine ring which bears two ketones.
Pharmacology
IndicationUsed in the control of absence (petit mal) seizures that are refractory to treatment with other medications.
PharmacodynamicsParamethadione and trimethadione are anticonvulsants indicated in the control of absence (petit mal) seizures that are refractory to treatment with other medications. Dione anticonvulsants are used in the treatment of epilepsy. They act on the central nervous system (CNS) to reduce the number of seizures.
Mechanism of actionDione anticonvulsants reduce T-type calcium currents in thalamic neurons, including thalamic relay neurons. It does so via the inhibition of voltage dependent T-type calcium channels. This raises the threshold for repetitive activity in the thalamus, and inhibits corticothalamic transmission. Thus, the abnormal thalamocortical rhythmicity, which is thought to underlie the 3-Hz spike-and-wave discharge seen on electroencephalogram(EEG) with absence seizures, is dampened.
AbsorptionNot Available
Volume of distributionNot Available
Protein binding90%
Metabolism
SubstrateEnzymesProduct
Trimethadione
dimethadioneDetails
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicitySymptoms of overdose include clumsiness or unsteadiness, coma, dizziness (severe), drowsiness (severe), nausea (severe), and problems with vision.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9954
Blood Brain Barrier + 0.9479
Caco-2 permeable + 0.5287
P-glycoprotein substrate Non-substrate 0.8304
P-glycoprotein inhibitor I Non-inhibitor 0.6154
P-glycoprotein inhibitor II Non-inhibitor 0.8382
Renal organic cation transporter Non-inhibitor 0.9503
CYP450 2C9 substrate Non-substrate 0.8289
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Substrate 0.5881
CYP450 1A2 substrate Non-inhibitor 0.9045
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Non-inhibitor 0.9231
CYP450 2C19 substrate Non-inhibitor 0.9026
CYP450 3A4 substrate Non-inhibitor 0.9694
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9361
Ames test Non AMES toxic 0.6493
Carcinogenicity Non-carcinogens 0.8515
Biodegradation Not ready biodegradable 0.7859
Rat acute toxicity 1.8563 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9961
hERG inhibition (predictor II) Non-inhibitor 0.9775
Pharmacoeconomics
Manufacturers
  • Abbott laboratories pharmaceutical products div
Packagers
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point46 °CPhysProp
water solubility5E+004 mg/LMERCK INDEX (1996)
logP0Not Available
Predicted Properties
PropertyValueSource
Water Solubility212.0ALOGPS
logP0.07ALOGPS
logP0.5ChemAxon
logS0.17ALOGPS
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area46.61 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity33.2 m3·mol-1ChemAxon
Polarizability13.59 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
Spectra
References
Synthesis ReferenceNot Available
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00392
PubChem Compound5576
PubChem Substance46504478
ChemSpider5374
BindingDB50019167
Therapeutic Targets DatabaseDAP001265
PharmGKBPA164744924
Drugs.comhttp://www.drugs.com/mtm/trimethadione.html
WikipediaTrimethadione
ATC CodesN03AC02
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
DisulfiramDisulfiram, a strong CYP2E1 inhibitor, may decrease the metabolism and clearance of Trimethadione, a CYP2E1 substrate. Consider alternate therapy or monitor for changes in Trimethadione therapeutic and adverse effects if Disulfiram is initiated, discontinued or dose changed.
TriprolidineThe CNS depressants, Triprolidine and Trimethadione, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
Food InteractionsNot Available

Targets

1. Voltage-dependent T-type calcium channel subunit alpha-1G

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent T-type calcium channel subunit alpha-1G O43497 Details

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
  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
  3. Shen H, Zhang B, Shin JH, Lei D, Du Y, Gao X, Wang Q, Ohlemiller KK, Piccirillo J, Bao J: Prophylactic and therapeutic functions of T-type calcium blockers against noise-induced hearing loss. Hear Res. 2007 Apr;226(1-2):52-60. Epub 2006 Dec 31. Pubmed
  4. Barton ME, Eberle EL, Shannon HE: The antihyperalgesic effects of the T-type calcium channel blockers ethosuximide, trimethadione, and mibefradil. Eur J Pharmacol. 2005 Oct 3;521(1-3):79-85. Epub 2005 Sep 19. Pubmed
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Enzymes

1. Cytochrome P450 2E1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2E1 P05181 Details

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. Epub 2009 Nov 24. Pubmed
  2. 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
  3. 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

2. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

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. Epub 2009 Nov 24. Pubmed
  2. 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
  3. 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

3. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

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. Epub 2009 Nov 24. Pubmed
  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

4. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

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. Epub 2009 Nov 24. Pubmed
  2. 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
  3. 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

5. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 Details

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. Epub 2009 Nov 24. Pubmed
  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

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Drug created on June 13, 2005 07:24 / Updated on December 10, 2013 22:43