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targets (1) enzymes (6)
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Identification
Name Mephenytoin
Accession Number DB00532 (APRD00512)
Type small molecule
Groups approved
Description

Mephenytoin is a hydantoin-derivative anticonvulsant used to control various partial seizures. It is generally reserved for treatment of individuals refractory to less toxic agents. Mephenytoin and oxazolidinedione derivatives are associated with higher incidences of blood dyscrasias compared to other anticonvulsants. As such, these agents should not be used concurrently.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Mephentoin
  • Methyl Hydantoin
  • Methylphenetoin
Brand names
  • Epiazin
  • Gerot-Epilan
  • Insulton
  • Mesdontoin
  • Mesontoin
  • Methoin
  • Metydan
  • Phenantoin
  • Sacerno
  • Sedantional
  • Sedantoin
  • Sedantoinal
  • Triantoin
Brand name mixtures Not Available
Categories
  • Anticonvulsants
CAS number 50-12-4
Weight Average: 218.2518
Monoisotopic: 218.105527702
Chemical Formula C12H14N2O2
InChI Key InChIKey=GMHKMTDVRCWUDX-UHFFFAOYSA-N
InChI
InChI=1S/C12H14N2O2/c1-3-12(9-7-5-4-6-8-9)10(15)14(2)11(16)13-12/h4-8H,3H2,1-2H3,(H,13,16)
Plain Text
IUPAC Name
5-ethyl-3-methyl-5-phenylimidazolidine-2,4-dione
SMILES
CCC1(NC(=O)N(C)C1=O)C1=CC=CC=C1
Plain Text
Mass Spec show (8.2 KB)
Taxonomy
Kingdom Organic
Classes
  • Phenethylamines
Substructures
  • Imidazolidinediones
  • Amino Ketones
  • Benzene and Derivatives
  • Ureas and Derivatives
  • Imidazolidines
  • Phenethylamines
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Carboxylic Acids and Derivatives
Pharmacology
Indication For the treatment of refractory partial epilepsy.
Pharmacodynamics 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.
Mechanism of action 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.
Absorption Not Available
Volume of distribution
  • 1.4 L/kg
Protein binding Not Available
Metabolism
Enzyme Metabolite Reaction Km Vmax
Cytochrome P450 2C9 Nirvanol
Cytochrome P450 2C19 S-4-Hydroxymephenytoin
Cytochrome P450 2C19 4'-hydroxymephenytoin 4'-hydroxylation 30 0.0029
Cytochrome P450 2B6 Nirvanol
Cytochrome P450 2B6 S-nirvanol N-demethylation 564 0
Route of elimination Not Available
Half life Approximately 7 hours
Clearance Not Available
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
Packagers
Dosage forms Not Available
Prices Not Available
Patents Not Available
Properties
State solid
Melting point 135 oC
Experimental Properties
Property Value Source
water solubility 1270 mg/L PhysProp
logP 1.3 PhysProp
pKa 8.51 Various sources
Predicted Properties
Property Value Source
water solubility 9.70e-01 g/l ALOGPS
logP 1.64 ALOGPS
logP 1.67 ChemAxon Molconvert
logS -2.35 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 2 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 49.41 ChemAxon Molconvert
rotatable bond count 2 ChemAxon Molconvert
refractivity 59.54 ChemAxon Molconvert
polarizability 22.67 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00375 Link_out
PubChem Compound 4060 Link_out
PubChem Substance 46508677 Link_out
ChemSpider 3920 Link_out
Therapeutic Targets Database DAP000508 Link_out
PharmGKB PA450373 Link_out
Drug Product Database 0 Link_out
Drugs.com http://www.drugs.com/mtm/mephenytoin.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Mephenytoin Link_out
ATC Codes
  • N03AB04
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS show (73.1 KB)
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Sodium channel protein type 5 subunit alpha

Pharmacological action: yes
Actions: inhibitor

This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-resistant Na(+) channel isoform. This channel is responsible for the initial upstroke of the action potential in the electrocardiogram

Organism class: human
UniProt ID: Q14524 Link_out
Gene: SCN5A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Lenkowski PW, Ko SH, Anderson JD, Brown ML, Patel MK: Block of human NaV1.5 sodium channels by novel alpha-hydroxyphenylamide analogues of phenytoin. Eur J Pharm Sci. 2004 Apr;21(5):635-44. Pubmed
  2. Swadron SP, Rudis MI, Azimian K, Beringer P, Fort D, Orlinsky M: A comparison of phenytoin-loading techniques in the emergency department. Acad Emerg Med. 2004 Mar;11(3):244-52. Pubmed
  3. 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 2C19

Actions: substrate, inhibitor

Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine

UniProt ID: P33261 Link_out
Gene: CYP2C19 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  3. 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
  4. Zhang T, Zhu Y, Gunaratna C: Rapid and quantitative determination of metabolites from multiple cytochrome P450 probe substrates by gradient liquid chromatography-electrospray ionization-ion trap mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2002 Nov 25;780(2):371-9. Pubmed

2. Cytochrome P450 2B6

Actions: substrate

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 unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20813 Link_out
Gene: CYP2B6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. Pivi Taavitsainen. (2000). Cytochrome P450 isoform-specific in vitro methods to predict drug metabolism and interactions. Department of Pharmacology and Toxicology, University of Oulu. Source
  3. Lewis DF, Modi S, Dickins M: Structure-activity relationship for human cytochrome P450 substrates and inhibitors. Drug Metab Rev. 2002 Feb-May;34(1-2):69-82. Pubmed
  4. Heyn H, White RB, Stevens JC: Catalytic role of cytochrome P4502B6 in the N-demethylation of S-mephenytoin. Drug Metab Dispos. 1996 Sep;24(9):948-54. Pubmed

3. Cytochrome P450 1A2

Actions: substrate

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 unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Coller JK, Somogyi AA, Bochner F: Comparison of (S)-mephenytoin and proguanil oxidation in vitro: contribution of several CYP isoforms. Br J Clin Pharmacol. 1999 Aug;48(2):158-67. Pubmed
  2. Koyama E, Chiba K, Tani M, Ishizaki T: Reappraisal of human CYP isoforms involved in imipramine N-demethylation and 2-hydroxylation: a study using microsomes obtained from putative extensive and poor metabolizers of S-mephenytoin and eleven recombinant human CYPs. J Pharmacol Exp Ther. 1997 Jun;281(3):1199-210. Pubmed

4. Cytochrome P450 2D6

Actions: substrate

Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Koyama E, Chiba K, Tani M, Ishizaki T: Reappraisal of human CYP isoforms involved in imipramine N-demethylation and 2-hydroxylation: a study using microsomes obtained from putative extensive and poor metabolizers of S-mephenytoin and eleven recombinant human CYPs. J Pharmacol Exp Ther. 1997 Jun;281(3):1199-210. Pubmed

5. Cytochrome P450 2C8

Actions: substrate

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 unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti- cancer drug paclitaxel (taxol)

UniProt ID: P10632 Link_out
Gene: CYP2C8
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

6. Cytochrome P450 2C9

Actions: substrate

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 unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on August 03, 2011 16:05

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.