Identification

Name
Mephenytoin
Accession Number
DB00532  (APRD00512)
Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Description

Mephenytoin is used for the treatment of refractory partial epilepsy. Mephenytoin is a solid. This compound belongs to the phenylhydantoins. These are heterocyclic aromatic compounds containing an imiazolidinedione moiety substituted by a phenyl group. Mephenytoin is known to target sodium channel protein type 5 subunit alpha. Cytochrome P450 2C19, Cytochrome P450 2C8, Cytochrome P450 2C9, Cytochrome P450 2B6, Cytochrome P450 1A2, and Cytochrome P450 2D6 are known to metabolize mephenytoin. Mephenytoin is a hydantoin-derivative anticonvulsant used to control various partial seizures. Mephenytoin and oxazolidinedione derivatives are associated with higher incidences of blood dyscrasias compared to other anticonvulsants. It is still studied largely because of its interesting hydroxylation polymorphism.

Structure
Thumb
Synonyms
Not Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
MesantoinTablet100 mg/1OralNovartis1946-10-232010-08-10Us
International/Other Brands
Mesantoin (Novartis)
Categories
UNII
R420KW629U
CAS number
50-12-4
Weight
Average: 218.2518
Monoisotopic: 218.105527702
Chemical Formula
C12H14N2O2
InChI Key
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)
IUPAC Name
5-ethyl-3-methyl-5-phenylimidazolidine-2,4-dione
SMILES
CCC1(NC(=O)N(C)C1=O)C1=CC=CC=C1

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.

TargetActionsOrganism
ASodium channel protein type 5 subunit alpha
inhibitor
Human
UNuclear receptor subfamily 1 group I member 2
activator
Human
Absorption
Not Available
Volume of distribution
  • 1.4 L/kg
Protein binding
Not Available
Metabolism
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
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Cytochrome P450 2C19CYP2C19*3(A;A)A Allele, homozygoteEffect Directly StudiedPatients with this genotype have reduced metabolism of mephenytoin.Details
Cytochrome P450 2C19CYP2C19*8(C;C) / (C;T)T > CEffect Directly StudiedPatients with this genotype have reduced metabolism of mephenytoin.Details
Cytochrome P450 2C19CYP2C19*7(A;A) / (A;T)T > AEffect Directly StudiedPatients with this genotype have reduced metabolism of mephenytoin.Details
Cytochrome P450 2C19CYP2C19*2ANot Available681G>AEffect InferredPoor metabolizer, lower dose requirementDetails
Cytochrome P450 2C19CYP2C19*2BNot Available681G>AEffect InferredPoor metabolizer, lower dose requirementDetails
Cytochrome P450 2C19CYP2C19*4Not Available1A>GEffect InferredPoor metabolizer, lower dose requirementDetails
Cytochrome P450 2C19CYP2C19*5Not Available1297C>TEffect InferredPoor metabolizer, lower dose requirementDetails
Cytochrome P450 2C19CYP2C19*6Not Available395G>AEffect InferredPoor metabolizer, lower dose requirementDetails
Cytochrome P450 2C19CYP2C19*7Not Available19294T>AEffect InferredPoor metabolizer, lower dose requirementDetails
Cytochrome P450 2C19CYP2C19*22Not Available557G>C / 991A>GEffect InferredPoor metabolizer, lower dose requirementDetails
Cytochrome P450 2C19CYP2C19*24Not Available99C>T / 991A>G  … show all Effect InferredPoor metabolizer, lower dose requirementDetails
Cytochrome P450 2C19CYP2C19*35Not Available12662A>GEffect InferredPoor metabolizer, lower dose requirementDetails

Interactions

Drug Interactions
DrugInteraction
AbirateroneThe serum concentration of Mephenytoin can be increased when it is combined with Abiraterone.
Acetyl sulfisoxazoleThe metabolism of Mephenytoin can be decreased when combined with Acetyl sulfisoxazole.
AlimemazineThe risk or severity of adverse effects can be increased when Mephenytoin is combined with Alimemazine.
AlprazolamThe risk or severity of adverse effects can be increased when Alprazolam is combined with Mephenytoin.
AmikacinThe risk or severity of adverse effects can be increased when Mephenytoin is combined with Amikacin.
AmitriptylineThe risk or severity of adverse effects can be increased when Amitriptyline is combined with Mephenytoin.
AmphetamineThe risk or severity of adverse effects can be increased when Amphetamine is combined with Mephenytoin.
ApalutamideThe serum concentration of Mephenytoin can be decreased when it is combined with Apalutamide.
AprepitantThe metabolism of Mephenytoin can be increased when combined with Aprepitant.
ArmodafinilThe metabolism of Mephenytoin can be decreased when combined with Armodafinil.
Food Interactions
Not Available

References

General References
Not Available
External Links
Human Metabolome Database
HMDB0014673
KEGG Drug
D00375
PubChem Compound
4060
PubChem Substance
46508677
ChemSpider
3920
ChEBI
6757
ChEMBL
CHEMBL861
Therapeutic Targets Database
DAP000508
PharmGKB
PA450373
Drugs.com
Drugs.com Drug Page
Wikipedia
Mephenytoin
ATC Codes
N03AB04 — MephenytoinN03AB54 — Mephenytoin, combinations
MSDS
Download (73.1 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
Not AvailableRecruitingOtherHealthy Volunteers1

Pharmacoeconomics

Manufacturers
  • Novartis pharmaceuticals corp
Packagers
  • Physicians Total Care Inc.
Dosage forms
FormRouteStrength
TabletOral100 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)135 °CPhysProp
water solubility1270 mg/LNot Available
logP1.69SANGSTER (1994)
pKa8.51TOMLINSON,E & HAFKENSCHEID,TL (1986)
Predicted Properties
PropertyValueSource
Water Solubility0.97 mg/mLALOGPS
logP1.64ALOGPS
logP1.67ChemAxon
logS-2.4ALOGPS
pKa (Strongest Acidic)11.18ChemAxon
pKa (Strongest Basic)-8.1ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area49.41 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity59.54 m3·mol-1ChemAxon
Polarizability22.67 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9771
Caco-2 permeable+0.6007
P-glycoprotein substrateNon-substrate0.5353
P-glycoprotein inhibitor INon-inhibitor0.8782
P-glycoprotein inhibitor IINon-inhibitor0.8593
Renal organic cation transporterNon-inhibitor0.9017
CYP450 2C9 substrateNon-substrate0.7827
CYP450 2D6 substrateNon-substrate0.9117
CYP450 3A4 substrateNon-substrate0.6645
CYP450 1A2 substrateNon-inhibitor0.9046
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9232
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-inhibitor0.8812
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9185
Ames testNon AMES toxic0.8301
CarcinogenicityNon-carcinogens0.7739
BiodegradationNot ready biodegradable0.9654
Rat acute toxicity2.3788 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9518
hERG inhibition (predictor II)Non-inhibitor0.8827
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (8.17 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - EI-BGC-MSsplash10-0f79-2900000000-af8712fc36e2b911e9a8
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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0159-3901000000-d726d8591f6fd6b87a0a

Taxonomy

Description
This compound belongs to the class of organic compounds known as phenylhydantoins. These are heterocyclic aromatic compounds containing an imiazolidinedione moiety substituted by a phenyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Azolidines
Sub Class
Imidazolidines
Direct Parent
Phenylhydantoins
Alternative Parents
Phenylimidazolidines / Alpha amino acids and derivatives / N-acyl ureas / Benzene and substituted derivatives / Dicarboximides / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives
show 1 more
Substituents
5-phenylhydantoin / Phenylimidazolidine / Alpha-amino acid or derivatives / N-acyl urea / Ureide / Monocyclic benzene moiety / Benzenoid / Dicarboximide / Urea / Carbonic acid derivative
show 11 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated sodium channel activity involved in sa node cell action potential
Specific Function
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 pr...
Gene Name
SCN5A
Uniprot ID
Q14524
Uniprot Name
Sodium channel protein type 5 subunit alpha
Molecular Weight
226937.475 Da
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:15066664]
  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:15001403]
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Activator
General Function
Zinc ion binding
Specific Function
Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism an...
Gene Name
NR1I2
Uniprot ID
O75469
Uniprot Name
Nuclear receptor subfamily 1 group I member 2
Molecular Weight
49761.245 Da
References
  1. Kobayashi K, Yamagami S, Higuchi T, Hosokawa M, Chiba K: Key structural features of ligands for activation of human pregnane X receptor. Drug Metab Dispos. 2004 Apr;32(4):468-72. [PubMed:15039302]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
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 im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
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:19515014]
  2. 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]
  3. 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:12401364]
  4. Ghahramani P, Ellis SW, Lennard MS, Ramsay LE, Tucker GT: Cytochromes P450 mediating the N-demethylation of amitriptyline. Br J Clin Pharmacol. 1997 Feb;43(2):137-44. [PubMed:9131945]
  5. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
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
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
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:19515014]
  2. 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:11996013]
  3. 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:8886603]
  4. Source [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
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:10417492]
  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:9190854]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
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...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
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:9190854]
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. 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. NCBI Cytochrome P450 CYP2C8 Profile [Link]
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
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
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:19515014]

Drug created on June 13, 2005 07:24 / Updated on September 21, 2018 00:02