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Identification
NamePhenytoin
Accession NumberDB00252  (APRD00241)
Typesmall molecule
Groupsapproved
Description

An anticonvulsant that is used in a wide variety of seizures. It is also an anti-arrhythmic and a muscle relaxant. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. The mechanism of its muscle relaxant effect appears to involve a reduction in the sensitivity of muscle spindles to stretch. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
5,5-Diphenyl-imidazolidine-2,4-dioneNot AvailableNot Available
5,5-diphenylimidazolidine-2,4-dioneNot AvailableNot Available
5,5-diphenyltetrahydro-1H-2,4-imidazoledione Not AvailableNot Available
FenitoinaSpanishINN
PhenytoineFrenchINN
PhenytoinumLatinINN
Salts
Name/CAS Structure Properties
Phenytoin Sodium
Thumb
  • InChI Key: FJPYVLNWWICYDW-UHFFFAOYSA-M
  • Monoisotopic Mass: 274.071822281
  • Average Mass: 274.2498
DBSALT000139
Brand names
NameCompany
DilantinNot Available
Dilantin-125Not Available
Epanutin Pfizer
EptoinNot Available
PhenytekMylan Laboratories
Brand mixtures
Brand NameIngredients
Dilantin W Phenobarbital 15mgPhenobarbital + Phenytoin Sodium
Dilantin W Phenobarbital 30mg CapPhenobarbital + Phenytoin Sodium
Categories
CAS number57-41-0
WeightAverage: 252.268
Monoisotopic: 252.089877638
Chemical FormulaC15H12N2O2
InChI KeyCXOFVDLJLONNDW-UHFFFAOYSA-N
InChI
InChI=1S/C15H12N2O2/c18-13-15(17-14(19)16-13,11-7-3-1-4-8-11)12-9-5-2-6-10-12/h1-10H,(H2,16,17,18,19)
IUPAC Name
5,5-diphenylimidazolidine-2,4-dione
SMILES
O=C1NC(=O)C(N1)(C1=CC=CC=C1)C1=CC=CC=C1
Mass Specshow(9.46 KB)
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassAzolidines
SubclassImidazolidines
Direct parentPhenylhydantoins
Alternative parentsDiphenylmethanes; Phenylimidazolidines; Ureides; N-unsubstituted Carboxylic Acid Imides; Secondary Carboxylic Acid Amides; Polyamines; Carboxylic Acids
Substituentsphenylimidazolidine; ureide; benzene; carboxylic acid imide, n-unsubstituted; secondary carboxylic acid amide; carboxamide group; carboxylic acid derivative; polyamine; carboxylic acid; organonitrogen compound
Classification descriptionThis compound belongs to the phenylhydantoins. These are heterocyclic aromatic compounds containing an imiazolidinedione moiety substituted by a phenyl group.
Pharmacology
IndicationFor the control of generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery.
PharmacodynamicsPhenytoin 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. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonic-clonic (grand mal) seizures. Phenytoin acts to dampen the unwanted, runaway brain activity seen in seizure by reducing electrical conductance among brain cells. It lacks the sedation effects associated with phenobarbital. There are some indications that phenytoin has other effects, including anxiety control and mood stabilization, although it has never been approved for those purposes by the FDA. Phenytoin is primarily metabolized by CYP2C9.
Mechanism of actionPhenytoin acts on sodium channels on the neuronal cell membrane, limiting the spread of seizure activity and reducing seizure propagation. By promoting sodium efflux from neurons, phenytoin 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 post-tetanic potentiation at synapses. Loss of post-tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas.
AbsorptionBioavailability 70-100% oral, 24.4% for rectal and intravenous administration. Rapid rate of absorption with peak blood concentration expected in 1½ to 3 hours.
Volume of distributionNot Available
Protein bindingHighly protein bound, 90%
Metabolism

Primarily hepatic. The majority of the dose (up to 90%) is metabolized to 5-(4'-hydroxyphenyl)-5-phenylhydantoin (p-HPPH). This metabolite undergoes further glucuronidation and is excreted into the urine. CYP2C19 and CYP2C9 catalyze the aforementioned reaction.

SubstrateEnzymesProduct
Phenytoin
3',4'-DihydrodiolDetails
Phenytoin
3'-HPPHDetails
Phenytoin
4'-HPPHDetails
Phenytoin
Phenytoin arene-oxideDetails
Phenytoin
Not Available
Phenytoin catecholDetails
Phenytoin
Not Available
Phenytoin quinoneDetails
Phenytoin catechol
Phenytoin methylcatecholDetails
Phenytoin arene-oxide
Phenytoin dihydrodiolDetails
Phenytoin arene-oxide
Not Available
HydroxyphenytoinDetails
Hydroxyphenytoin
Phenytoin catecholDetails
Phenytoin catechol
Phenytoin quinoneDetails
Hydroxyphenytoin
Hydroxyphenytoin-O-glucuronideDetails
3'-HPPH
3',4'-diHPPHDetails
4'-HPPH
3',4'-diHPPHDetails
Route of eliminationMost of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion.
Half life22 hours (range of 7 to 42 hours)
ClearanceNot Available
ToxicityOral, mouse: LD50 = 150 mg/kg; Oral, rat: LD50 = 1635 mg/kg. Symptoms of overdose include coma, difficulty in pronouncing words correctly, involuntary eye movement, lack of muscle coordination, low blood pressure, nausea, sluggishness, slurred speech, tremors, and vomiting.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Phenytoin (Antiarrhythmic) Action PathwayDrug actionSMP00327
Fosphenytoin (Antiarrhythmic) Action PathwayDrug actionSMP00326
Fosphenytoin (Antiarrhythmic) Metabolism PathwayDrug metabolismSMP00618
SNP Mediated Effects
Interacting Gene/EnzymeSNP RS IDAllele nameDefining changeEffectReference(s)
Cytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
rs1057910 CYP2C9*1C AllelePoor drug metabolizer, lower dose requirements15805193
Multidrug resistance protein 1
Gene symbol: ABCB1
UniProt: P08183
rs1045642 MDR1*TT Allele (C3435T)Increased phenytoin effects due to higher plasma phenytoin levels11908757
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9909
Blood Brain Barrier + 0.976
Caco-2 permeable + 0.8867
P-glycoprotein substrate Non-substrate 0.5593
P-glycoprotein inhibitor I Non-inhibitor 0.8782
P-glycoprotein inhibitor II Non-inhibitor 0.987
Renal organic cation transporter Non-inhibitor 0.8995
CYP450 2C9 substrate Non-substrate 0.733
CYP450 2D6 substrate Substrate 0.8911
CYP450 3A4 substrate Non-substrate 0.7591
CYP450 1A2 substrate Non-inhibitor 0.9045
CYP450 2C9 substrate Non-inhibitor 0.8304
CYP450 2D6 substrate Non-inhibitor 0.935
CYP450 2C19 substrate Non-inhibitor 0.9026
CYP450 3A4 substrate Non-inhibitor 0.8309
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8994
Ames test Non AMES toxic 0.9132
Carcinogenicity Non-carcinogens 0.855
Biodegradation Not ready biodegradable 0.992
Rat acute toxicity 2.1567 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9793
hERG inhibition (predictor II) Non-inhibitor 0.8916
Pharmacoeconomics
Manufacturers
  • Parke davis div warner lambert co
  • Actavis mid atlantic llc
  • Taro pharmaceutical industries ltd
  • Vistapharm inc
  • Wockhardt eu operations (swiss) ag
  • Pfizer pharmaceuticals ltd
  • Lannett co inc
  • Amneal pharmaceuticals ny llc
  • Barr laboratories inc
  • Mylan pharmaceuticals inc
  • Pliva inc
  • Sun pharmaceutical industries ltd
  • Wockhardt ltd
  • Wockhardt usa inc
  • Watson laboratories inc
  • Pharmeral inc
  • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
  • Parke davis pharmaceutical research div warner lambert co
  • App pharmaceuticals llc
  • Baxter healthcare corp
  • Hikma farmaceutica (portugal) sa
  • Hospira inc
  • Marsam pharmaceuticals llc
  • Pharmaforce inc
  • Smith and nephew solopak div smith and nephew
  • Solopak medical products inc
  • Warner chilcott div warner lambert co
Packagers
Dosage forms
FormRouteStrength
CapsuleOral30 mg, 100 mg, 200 mg, 300 mg
Injection, solutionOral50 mg/mL
TabletOral125 mg/5 mL
Tablet, chewableOral50 mg
Prices
Unit descriptionCostUnit
Dilantin 125 mg/5ml Suspension 237ml Bottle69.28USDbottle
Phenytoin Sodium 50 mg/ml2.64USDml
Phenytek 300 mg capsule1.47USDcapsule
Phenytoin sod ext 300 mg capsule1.2USDcapsule
Phenytoin sodium powder1.16USDg
Phenytek 200 mg capsule0.98USDcapsule
Phenytoin 50 mg/ml ampul0.96USDml
Phenytoin sod ext 200 mg capsule0.8USDcapsule
Phenytoin 50 mg/ml vial0.67USDml
Phenytoin 100 mg/2 ml vial0.6USDml
Dilantin Infatabs 50 mg Chew Tabs0.6USDtab
Dilantin 100 mg capsule0.51USDcapsule
Phenytoin 100 mg/4 ml susp0.48USDml
Dilantin 30 mg capsule0.46USDcapsule
Phenytoin 250 mg/5 ml vial0.45USDml
Dilantin 50 mg infatab0.44USDeach
Dilantin 100 mg kapseal0.39USDeach
Dilantin 30 mg kapseal0.39USDeach
Phenytoin Sodium Extended 100 mg capsule0.36USDcapsule
Phenytoin sod ext 100 mg capsule0.34USDcapsule
Phenytoin powder0.23USDg
Phenytoin 125 mg/5ml Suspension0.15USDml
Dilantin Infatabs 50 mg Chewable Tablet0.08USDtablet
Dilantin 100 mg Capsule0.08USDcapsule
Dilantin 30 mg Capsule0.06USDcapsule
Dilantin-125 25 mg/ml Suspension0.05USDml
Dilantin-30 6 mg/ml Suspension0.04USDml
Taro-Phenytoin 25 mg/ml Suspension0.03USDml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point286 °CPhysProp
water solubility32 mg/L (at 22 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP2.47HANSCH,C ET AL. (1995)
Caco2 permeability-4.57ADME Research, USCD
pKa8.33SANGSTER (1994)
Predicted Properties
PropertyValueSource
water solubility7.11e-02 g/lALOGPS
logP2.26ALOGPS
logP2.15ChemAxon
logS-3.5ALOGPS
pKa (strongest acidic)9.47ChemAxon
pKa (strongest basic)-9ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count2ChemAxon
hydrogen donor count2ChemAxon
polar surface area58.2ChemAxon
rotatable bond count2ChemAxon
refractivity70.18ChemAxon
polarizability25.48ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Mahdi B. Fawzi, Anne K. Taylor, “Parenteral phenytoin preparations.” U.S. Patent US4642316, issued April, 1981.

US4642316
General Reference
  1. https://www.pharmgkb.org/pathway/PA145011115
External Links
ResourceLink
KEGG DrugD00512
KEGG CompoundC07443
PubChem Compound1775
PubChem Substance46508847
ChemSpider1710
ChEBI8107
ChEMBLCHEMBL16
Therapeutic Targets DatabaseDAP000130
PharmGKBPA450947
IUPHAR2624
Guide to Pharmacology2624
Drug Product Database780626
RxListhttp://www.rxlist.com/cgi/generic/phenyt.htm
Drugs.comhttp://www.drugs.com/cdi/phenytoin.html
PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/dil1136.shtml
WikipediaPhenytoin
ATC CodesN03AB02N03AB04N03AB05
AHFS Codes
  • 28:12.12
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(73.7 KB)
Interactions
Drug Interactions
Drug
AbirateroneStrong CYP3A4 inducers may decrease levels of abiraterone. Monitor concomitant therapy closely.
AcenocoumarolIncreased hydantoin levels and risk of bleeding
ado-trastuzumab emtansineAvoid combination with phenytoin and other strong CYP3A4 inducers due to the likely increase in metabolism of ado-trastuzumab emtansine to its active component, DM1.
AlprazolamPhenytoin may increase the metabolism of alprazolam via CYP3A4.
AminophyllineDecreased effect of both products
AmiodaroneAmiodarone may increase the therapeutic and adverse effects of phenytoin.
AnisindioneIncreased hydantoin levels and risk of bleeding
AprepitantThe CYP3A4 inducer, phenytoin, may decrease the effect of aprepitant.
AsenapinePhenytoin is a CYP1A2 inducer and may increase metabolism of asenapine.
AtracuriumPhenytoin decreases the effect of the muscle relaxant
AxitinibAvoid combination with phenytoin and other strong, moderate, or weak CYP3A4 inducers due to the likely decreased levels of axitinib.
BetamethasoneThe enzyme inducer, phenytoin, may decrease the effect of the corticosteroid, betamethasone.
BleomycinThe antineoplasic agent decreases the effect of hydantoin
BoceprevirStrong CYP3A4 inducers will decrease levels of boceprevir. Concomitant therapy is contraindicated.
CabazitaxelConcomitant therapy with a strong CYP3A inducer may decrease concentrations of cabazitaxel. Avoid concomitant therapy.
CanagliflozinNonselective inducers of UGT enzymes may decrease levels of canagliflozin, thus decreasing efficacy. Consider increase the dose to 300 mg once daily.
CapecitabineCapecitabine increases the effect of hydantoin
CarboplatinThe antineoplasic agent decreases the effect of hydantoin
CarmustineThe antineoplasic agent decreases the effect of hydantoin
ChloramphenicolIncreases phenytoin, modifies chloramphenicol
ChlordiazepoxidePhenytoin may increase the metabolism of chlordiazepoxide via CYP3A4.
ChlorotrianiseneThe enzyme inducer, phenytoin, decreases the effect of the hormone agent, chlorotrianisene.
ChlorphenamineThe antihistamine increases the effect of hydantoin
CimetidineCimetidine may increase the therapeutic effect of phenytoin.
CiprofloxacinCiprofloxacin may decrease the therapeutic effect of phenytoin.
CisplatinThe antineoplasic agent decreases the effect of hydantoin
ClarithromycinClarithromycin may increase the therapeutic and adverse effects of phenytoin.
ClomifeneThe enzyme inducer, phenytoin, decreases the effect of the hormone agent, clomifene.
ClorazepatePhenytoin may increase the metabolism of clorazepate via CYP3A4.
ClozapinePhenytoin may decrease the effect of clozapine.
ColesevelamColesevelam may decrease the serum concentration of Phenytoin. Phenytoin should be administered at least 4 hours prior to colesevelam.
Conjugated EstrogensThe enzyme inducer, phenytoin, decreases the effect of the hormone agent, conjugated estrogens.
Cortisone acetateThe enzyme inducer, phenytoin, may decrease the effect of the corticosteroid, cortisone acetate.
CyclosporineThe hydantoin decreases the effect of cyclosporine
DabrafenibStrong CYP3A4 inducers may decrease levels of dabrafenib. Consider alternate therapy.
DasatinibPhenytoin may decrease the serum level and efficacy of dasatinib.
DelavirdineThe anticonvulsant, phenytoin, decreases the effect of delavirdine.
DexamethasoneThe enzyme inducer, phenytoin, may decrease the effect of the corticosteroid, dexamethasone.
DiazepamPhenytoin may increase the metabolism of diazepam via CYP3A4.
DiazoxideDiazoxide decreases the efficacy of phenytoin.
DicoumarolIncreased hydantoin levels and risk of bleeding
DiethylstilbestrolThe enzyme inducer, phenytoin, decreases the effect of the hormone agent, diethylstilbestrol.
DisopyramideThe hydantoin decreases the effect of disopyramide
DisulfiramDisulfiram may increase the therapeutic and adverse effects of phenytoin.
DopamineRisk of severe hypotension
Doxacurium chloridePhenytoin decreases the effect of the muscle relaxant
DoxycyclineThe anticonvulsant, phenytoin, may decrease the effect of doxycycline.
DyphyllineDecreased effect of both products
EstradiolThe enzyme inducer, phenytoin, decreases the effect of the hormone agent, estradiol.
Estradiol valerate/DienogestAffects CYP3A4 metabolism, decreases or effects levels of Estradiol valerate/Dienogest.
EstriolThe enzyme inducer, phenytoin, decreases the effect of the hormone agent, estriol.
EstroneThe enzyme inducer, phenytoin, decreases the effect of the hormone agent, estrone.
EstropipateThe enzyme inducer, phenytoin, decreases the effect of the hormone agent, estropipate.
Ethinyl EstradiolThis product may cause a slight decrease of contraceptive effect
EtravirineEtravirine, when used concomitantly with phenytoin, may experience a decrease in serum concentration. It is recommended to avoid concurrent therapy.
EzogabineEzogabine increases the clearance of phenytoin (30%). The mechanism of this interaction is unknown.
FelbamateIncreased phenytoin levels and decreased felbamate levels
FelodipineThe hydantoin decreases the effect of felodipine
FluconazoleFluconazole may increase the therapeutic and adverse effects of phenytoin.
FludrocortisoneThe enzyme inducer, phenytoin, may decrease the effect of the corticosteroid, fludrocortisone.
FluorouracilFluorouracil increases the effect of hydantoin
FluoxetineFluoxetine increases the effect of phenytoin
FlurazepamPhenytoin may increase the metabolism of flurazepam via CYP3A4.
FluvoxamineFluvoxamine may increase the therapeutic effect of phenytoin.
Folic AcidFolic acid may decrease the levels of phenytoin.
FurosemideThe hydantoin decreases the effect of furosemide
GabapentinGabapentin may increase the therapeutic and adverse effects of phenytoin.
GefitinibThe CYP3A4 inducer, phenytoin, may decrease the serum concentration and therapeutic effects of gefitinib.
HydrocortisoneThe enzyme inducer, phenytoin, may decrease the effect of the corticosteroid, hydrocortisone.
ImatinibThe hydantoin decreases the levels of imatinib
IrinotecanThe hydantoin decreases the effect of irinotecan
IsoniazidIsoniazid increases the effect of phenytoin in 20% of patients
ItraconazolePhenytoin decreases the effect of itraconazole
IvacaftorStrong CYP3A4 inducers may decrease levels of ivacaftor. Monitor concomitant therapy closely.
L-DOPAThe hydantoin decreases the effect of levodopa
LamotriginePhenytoin may reduce levels of lamotrigine
LevonorgestrelPhenytoin decreases the contraceptive effect
LopinavirLevels of both drugs are affected
MebendazoleThe hydantoin decreases the efficiency of mebendazole
Medroxyprogesterone AcetateThe enzyme inducer, phenytoin, may decrease the effect of medroxyprogesterone.
Megestrol acetateThe enzyme inducer, phenytoin, may decrease the effect of megestrol.
MestranolThis product may cause a slight decrease of contraceptive effect
MethadoneThe hydantoin decreases the effect of methadone
MethotrexateThe antineoplasic agent decreases the effect of hydantoin
MethoxsalenThe hydantoin decreases the effect of psoralene
MethylprednisoloneThe enzyme inducer, phenytoin, may decrease the effect of the corticosteroid, methylprednisolone.
MetocurinePhenytoin decreases the effect of the muscle relaxant
MetyraponeThe combination renders the test invalid
MexiletineThe hydantoin decreases the effect of mexiletine
MidazolamPhenytoin may increase the metabolism of midazolam via CYP3A4.
MirtazapineThe hydantoins may reduce mirtazapine plasma concentrations and pharmacological effects
MivacuriumPhenytoin decreases the effect of the muscle relaxant
NisoldipinePhenytoin decreases the efficiency of nisoldipine
NorethindroneThis product may cause a slight decrease of contraceptive effect
OmeprazoleOmeprazole increases the effect of hydantoin
OxcarbazepineOxcarbazepine increases the effect of hydantoin
OxtriphyllineDecreased effect of both products
OxyphenbutazoneThe NSAID, oxphenbutazone, may increase the therapeutic and adverse effects of phenytoin.
PancuroniumPhenytoin decreases the effect of the muscle relaxant
ParamethasoneThe enzyme inducer, phenytoin, may decrease the effect of the corticosteroid, paramethasone.
PerampanelAvoid combination with phenytoin or other strong CYP3A4 inducers due to the likely decrease of perampanel concentration. If the combination must be used, an increase in perampanel dose is necessary.
PhenylbutazoneThe NSAID, phenylbutazone, may increase the therapeutic and adverse effects of phenytoin.
PonatinibStrong CYP3A4 inducers may decrease levels of ponatinib. Monitor concomitant therapy closely.
PonatinibStrong CYP3A4 inducers may decrease levels of ponatinib. Monitor concomitant therapy closely.
PosaconazoleModifications of drug levels for both agents
PraziquantelMarkedly lower praziquantel levels
PrednisoloneThe enzyme inducer, phenytoin, may decrease the effect of the corticosteroid, prednisolone.
PrednisoneThe enzyme inducer, phenytoin, may decrease the effect of the corticosteroid, prednisone.
QuetiapinePhenytoin decreases the effect of quetiapine
QuinestrolThe enzyme inducer, phenytoin, decreases the effect of the hormone agent, quinestrol.
QuinidineThe anticonvulsant, phenytoin, decreases the effect of quinidine.
RegorafenibStrong CYP3A4 inducers may decrease levels of regorafenib.
RifampicinRifampin may decrease the therapeutic and adverse effects of phenytoin.
RilpivirineStrong inducers of CYP3A4 decrease the exposure of rilpivirine thus decreasing efficacy.
RufinamideIncreases clearance of rufinamide thus decreasing plasma concentration of rufinamide.
SertralineSertraline increases the effect of hydantoin
SirolimusThe hydantoin decreases sirolimus levels
SucralfateSucralfate decreases the effect of hydantoin
SulfadiazineThe sulfonamide increases the effect of hydantoin
SulfamethizoleThe sulfonamide increases the effect of hydantoin
SunitinibPossible decrease in sunitinib levels
TacrolimusPhenytoin may decrease the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Phenytoin therapy is initiated, discontinued or altered.
TelithromycinPhenytoin may decrease the plasma concentration of Telithromycin by increasing its metabolism. Consider alternate therapy.
TemsirolimusPhenytoin may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.
TheophyllineDecreased effect of both products
ThiotepaPossible increase in thiotepa levels
TiclopidineTiclopidine may decrease the metabolism and clearance of phenytoin. Consider alternate therapy or monitor for adverse/toxic effects of phenytoin if ticlopidine is initiated, discontinued or dose changed.
TipranavirPhenytoin decreases the concentration of Tipranavir. Monitor for decreased Tipranavir efficacy.
TobramycinIncreased risk of nephrotoxicity
TofacitinibAvoid combination with phenytoin and other strong CYP3A4 inducers due to the potential decrease in tofacitinib serum levels.
TolbutamideTolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Phenytoin. Consider alternate therapy or monitor for changes in Phenytoin therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
TolvaptanPhenytoin is a CYP3A4 inducer and will decrease serum concentrations of tolvaptan and ultimately, its clinical effects.
TopiramateIncreased phenytoin/decreased topiramate
TramadolPhenytoin may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.
TrazodoneThe CYP3A4 inducer, Phenytoin, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Phenytoin is initiated, discontinued or dose changed.
TretinoinThe strong CYP2C8 inducer, Phenytoin, may increase the metabolism and clearance of oral Tretinoin. Consider alternate therapy to avoid failure of Tretinoin therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Phenytoin is initiated, discontinued or dose changed.
TriamcinoloneThe enzyme inducer, phenytoin, may decrease the effect of the corticosteroid, triamcinolone.
TriazolamPhenytoin may increase the metabolism of triazolam via CYP3A4.
TrimethoprimTrimethoprim increases the effect of hydantoin
TrioxsalenThe hydantoin decreases the effect of psoralene
TriprolidineThe CNS depressants, Triprolidine and Phenytoin, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
TubocurarinePhenytoin decreases the effect of the muscle relaxant
UlipristalConcomitant therapy with strong CYP3A4 inducers may decrease plasma concentrations of ulipristal and ultimately its effectiveness. Avoid combination therapy.
VandetanibDecreases levels of vandetanib by affecting CYP3A4 metabolism. Contraindicated.
VecuroniumPhenytoin decreases the effect of the muscle relaxant
VemurafenibStrong CYP3A4 inducers may decrease levels of vemurafenib. Monitor concomitant therapy closely.
VerapamilVerapamil may increase the serum concentration of Phenytoin by decreasing its metabolism. Monitor for changes in the therapeutic/adverse effects of Phenytoin if Verapamil is initiated, discontinued or dose changed.
VigabatrinVigabatrin reduces plasma levels of phenytoin by 16-20% which may be due to induction of CYP2C. Consider dosage adjustment.
VinblastineThe antineoplasic agent decreases the effect of hydantoin
VoriconazoleVoriconazole may increase the serum concentration of phenytoin by decreasing its metabolism. Phenytoin may increase the serum concentration of voriconazole by increasing its metabolism. Consider alternate antifungal therapy or monitor for voriconazole therapy failure and phenytoin toxicity.
WarfarinWarfarin may increase the serum concentration of phenytoin possibly by competing for CYP2C9 metabolism. Phenytoin may increase the anticoagulant effect of warfarin. Monitor phenytoin levels, prothrombin time, and therapeutic and adverse effects of both agents during concomitant therapy.
Food Interactions
  • Avoid alcohol.
  • Do not take calcium, aluminum, magnesium or Iron supplements within 2 hours of taking this medication.
  • Take with food to increase bioavailability and reduce irritation.

Targets

1. Sodium channel protein type 5 subunit alpha

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Sodium channel protein type 5 subunit alpha Q14524 Details

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

2. Sodium channel protein type 1 subunit alpha

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Sodium channel protein type 1 subunit alpha P35498 Details

References:

  1. Tate SK, Depondt C, Sisodiya SM, Cavalleri GL, Schorge S, Soranzo N, Thom M, Sen A, Shorvon SD, Sander JW, Wood NW, Goldstein DB: Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin. Proc Natl Acad Sci U S A. 2005 Apr 12;102(15):5507-12. Epub 2005 Apr 1. Pubmed
  2. Tate SK, Singh R, Hung CC, Tai JJ, Depondt C, Cavalleri GL, Sisodiya SM, Goldstein DB, Liou HH: A common polymorphism in the SCN1A gene associates with phenytoin serum levels at maintenance dose. Pharmacogenet Genomics. 2006 Oct;16(10):721-726. Pubmed
  3. Mantegazza M, Curia G, Biagini G, Ragsdale DS, Avoli M: Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders. Lancet Neurol. 2010 Apr;9(4):413-24. Pubmed

Enzymes

1. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor inducer

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

  1. Levy RH: Cytochrome P450 isozymes and antiepileptic drug interactions. Epilepsia. 1995;36 Suppl 5:S8-13. Pubmed
  2. 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
  3. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  4. Tate SK, Depondt C, Sisodiya SM, Cavalleri GL, Schorge S, Soranzo N, Thom M, Sen A, Shorvon SD, Sander JW, Wood NW, Goldstein DB: Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin. Proc Natl Acad Sci U S A. 2005 Apr 12;102(15):5507-12. Epub 2005 Apr 1. Pubmed
  5. 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. Komatsu T, Yamazaki H, Asahi S, Gillam EM, Guengerich FP, Nakajima M, Yokoi T: Formation of a dihydroxy metabolite of phenytoin in human liver microsomes/cytosol: roles of cytochromes P450 2C9, 2C19, and 3A4. Drug Metab Dispos. 2000 Nov;28(11):1361-8. Pubmed
  7. Lexicomp

2. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inducer

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 Details

References:

  1. Levy RH: Cytochrome P450 isozymes and antiepileptic drug interactions. Epilepsia. 1995;36 Suppl 5:S8-13. Pubmed
  2. 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
  3. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  4. 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
  5. Komatsu T, Yamazaki H, Asahi S, Gillam EM, Guengerich FP, Nakajima M, Yokoi T: Formation of a dihydroxy metabolite of phenytoin in human liver microsomes/cytosol: roles of cytochromes P450 2C9, 2C19, and 3A4. Drug Metab Dispos. 2000 Nov;28(11):1361-8. Pubmed
  6. Kaminsky LS, Zhang ZY: Human P450 metabolism of warfarin. Pharmacol Ther. 1997;73(1):67-74. Pubmed
  7. Lexicomp

3. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inducer

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  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. Epub 2009 Nov 24. Pubmed
  3. Lexicomp

4. Cytochrome P450 2B6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Cytochrome P450 2B6 P20813 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Lexicomp

5. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inducer

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. Lexicomp

6. Cytochrome P450 2C18

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C18 P33260 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

7. Cytochrome P450 3A5

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Cytochrome P450 3A5 P20815 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

8. Cytochrome P450 3A7

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Cytochrome P450 3A7 P24462 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

9. Cytochrome P450 11B1, mitochondrial

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 11B1, mitochondrial P15538 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

Carriers

1. Serum albumin

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Serum albumin P02768 Details

References:

  1. Chen J, Ohnmacht C, Hage DS: Studies of phenytoin binding to human serum albumin by high-performance affinity chromatography. J Chromatogr B Analyt Technol Biomed Life Sci. 2004 Sep 25;809(1):137-45. Pubmed
  2. Ohnmacht CM, Chen S, Tong Z, Hage DS: Studies by biointeraction chromatography of binding by phenytoin metabolites to human serum albumin. J Chromatogr B Analyt Technol Biomed Life Sci. 2006 May 19;836(1-2):83-91. Epub 2006 Apr 18. Pubmed

Transporters

1. Solute carrier organic anion transporter family member 1C1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Solute carrier organic anion transporter family member 1C1 Q9NYB5 Details

References:

  1. Westholm DE, Stenehjem DD, Rumbley JN, Drewes LR, Anderson GW: Competitive inhibition of organic anion transporting polypeptide 1c1-mediated thyroxine transport by the fenamate class of nonsteroidal antiinflammatory drugs. Endocrinology. 2009 Feb;150(2):1025-32. Epub 2008 Oct 9. Pubmed
  2. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. Pubmed

2. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. Baltes S, Gastens AM, Fedrowitz M, Potschka H, Kaever V, Loscher W: Differences in the transport of the antiepileptic drugs phenytoin, levetiracetam and carbamazepine by human and mouse P-glycoprotein. Neuropharmacology. 2007 Feb;52(2):333-46. Epub 2006 Oct 10. Pubmed
  2. Luna-Tortos C, Fedrowitz M, Loscher W: Several major antiepileptic drugs are substrates for human P-glycoprotein. Neuropharmacology. 2008 Dec;55(8):1364-75. Epub 2008 Sep 11. Pubmed

3. Canalicular multispecific organic anion transporter 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Canalicular multispecific organic anion transporter 1 Q92887 Details

References:

  1. Baltes S, Gastens AM, Fedrowitz M, Potschka H, Kaever V, Loscher W: Differences in the transport of the antiepileptic drugs phenytoin, levetiracetam and carbamazepine by human and mouse P-glycoprotein. Neuropharmacology. 2007 Feb;52(2):333-46. Epub 2006 Oct 10. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:08