Identification

Name
Phenytoin
Accession Number
DB00252
Description

Phenytoin is classified as a hydantoin derivative and despite its narrow therapeutic index, it is one of the most commonly used anticonvulsants.12,6,8 Since it's introduction about 80 years ago, phenytoin has not only been established as an effective anti-epileptic, but has also been investigated for several other indications such as bipolar disorder, retina protection, and wound healing.7,6

Clinicians are advised to initiate therapeutic drug monitoring in patients who require phenytoin since even small deviations from the recommended therapeutic range can lead to suboptimal treatment, or adverse effects.8,10 Both parenteral and oral formulations of phenytoin are available on the market.8

Type
Small Molecule
Groups
Approved, Vet approved
Structure
Thumb
Weight
Average: 252.268
Monoisotopic: 252.089877638
Chemical Formula
C15H12N2O2
Synonyms
  • 5,5-Diphenyl-imidazolidine-2,4-dione
  • 5,5-diphenylimidazolidine-2,4-dione
  • 5,5-diphenyltetrahydro-1H-2,4-imidazoledione
  • 5,5-Diphenyltetrahydro-1H-2,4-imidazoledione
  • Diphenylhydantoin
  • Fenitoina
  • Phentytoin
  • Phenytoin
  • Phenytoine
  • Phenytoinum
External IDs
  • NSC-8722

Pharmacology

Indication

Phenytoin is indicated to treat grand mal seizures, complex partial seizures, and to prevent and treat seizures during or following neurosurgery.14 Injectable phenytoin and Fosphenytoin, which is the phosphate ester prodrug formulation of phenytoin2, are indicated to treat tonic-clonic status epilepticus, and for the prevention and treatment of seizures occurring during neurosurgery.15

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Phenytoin is an anticonvulsant with a narrow therapeutic index.5 Although the recommended therapeutic range is cited to be between 10-20 mg/L, differences in albumin levels, genetics, comorbidities, and body composition can make achieving an ideal phenytoin dose challenging.5 For example, studies have confirmed that phenytoin metabolism is impacted by CYP2C9 genotype polymorphisms and possibly by CYP2C19 genotype polymorphisms (the latter has not been as extensively studied).5

It is worth nothing that although phenytoin is highly protein bound, only the fraction unbound is able to exert a pharmacological effect.17 Therefore, factors that reduce or increase the percentage of protein bound phenytoin (for example: concomitant administration of drugs that can cause displacement from protein binding sites) can have a marked impact on phenytoin therapy.4,17

Mechanism of action

Although phenytoin first appeared in the literature in 1946, it has taken decades for the mechanism of action to be more specifically elucidated.7 Although several scientists were convinced that phenytoin altered sodium permeability, it wasn’t until the 1980’s that this phenomenon was linked to voltage-gated sodium channels.7

Phenytoin is often described as a non-specific sodium channel blocker and targets almost all voltage-gated sodium channel subtypes.7 More specifically, phenytoin prevents seizures by inhibiting the positive feedback loop that results in neuronal propagation of high frequency action potentials.5,8,9

TargetActionsOrganism
ASodium channel protein type 5 subunit alpha
inhibitor
Humans
ASodium channel protein type 1 subunit alpha
inhibitor
Humans
UNuclear receptor subfamily 1 group I member 2Not AvailableHumans
USodium channel subunit beta-1Not AvailableHumans
USodium channel protein type 3 subunit alphaNot AvailableHumans
APotassium voltage-gated channel subfamily H member 2
inhibitor
Humans
AVoltage-dependent L-type calcium channel
inhibitor
Humans
ASodium channel protein type 2 subunit alpha
inhibitor
Humans
ASodium channel protein type 8 subunit alpha
inhibitor
Humans
UGABA(A) ReceptorNot AvailableHumans
Absorption

Given its narrow therapeutic index, therapeutic drug monitoring is recommended to help guide dosing.8,10 Phenytoin is completely absorbed.8 Peak plasma concentration is attained approximately 1.5-3 hours, and 4-12 hours after administration of the immediate release formulation and the extended release formulation, respectively.3,8 It should be noted that absorption can be markedly prolonged in situations of acute ingestion.8

Volume of distribution

The volume of distribution of phenytoin is reported to be approximately 0.75 L/kg.11

Protein binding

Phenytoin is roughly 90% protein bound.4

Metabolism

Phenytoin is extensively metabolized and is first transformed into a reactive arene oxide intermediate.12 It is thought that this reactive intermediate is responsible for many undesirable phenytoin adverse effects such as hepatotoxicity, SJS/TEN, and other idiosyncratic reactions.12 The arene oxide is metabolized to either a hydroxyphenytoin or phenytoin dihydrodiol metabolite, although the former accounts for about 90% of phenytoin metabolism.12

Interestingly, two stereoisomers of the hydroxyphenytoin metabolite are formed by CYP2C9 and CYP2C19: (R)-p-HPPH and (S)-p-HPPH.12 When CYP2C19 catalyzes the reaction, the ratio of stereoisomers is roughly 1:1, whereas when CYP2C9 catalyzes the reaction, the ratio heavily favours the "S" stereoisomer.12 Since the metabolism of phenytoin is in part influenced by genetic polymorphisms of CYP2C9 and CYP2C19, this ratio can be utilized to identify different genomic variants of the enzymes.5,6,12

EPHX1, CYP1A2, CYP2A6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP2E1 and CYP3A4 are responsible for producing the phenytoin dihydrodiol metabolite.12

Hydroxyphenytoin can be metabolized by CYP2C19, CYP3A5, CYP2C9, CYP3A4, CYP3A7, CYP2B6 and CYP2D6 to a phenytoin catechol metabolite or undergo glucuronidation by UGT1A6, UGT1A9, UGT1A1, and UGT1A4 to a glucuronide metabolite that can be eliminated in the urine.12 On the other hand, the phenytoin dihydrodiol entity is only transformed to the catechol metabolite.12

The catechol metabolite can undergo methylation by COMT and be subsequently eliminated in the urine, or can spontaneously oxidize to a phenytoin quinone (NQO1 can transform the quinone back to the catechol metabolite).12

Of note, although CYP2C18 is poorly expressed in the liver, the enzyme is active in the skin and is involved in the primary and secondary hydroxylation of phenytoin.12,13 This CYP2C18 mediated bioactivation may be linked to the manifestation of adverse cutaneous drug reactions associated with phenytoin.12

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Route of elimination

The majority of phenytoin is excreted as inactive metabolites in the bile.14,16 An estimated 1-5% of phenytoin is eliminated unchanged in the urine.8

Half-life

Oral administration: The half-life of phenytoin ranges from 7 to 42 hours, and is 22 hours on average.11,14

Intravenous administration: The half-life of phenytoin ranges from 10-15 hours.16

Clearance

The clearance of phenytoin is non-linear.10 At lower serum concentrations (less than 10 mg/L), elimination is characterized by first order kinetics.3 As plasma concentrations increase, the kinetics shift gradually towards zero-order, and finally reach zero-order kinetics once the system is saturated.3

Adverse Effects
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Toxicity

The experience of phenytoin toxicity is not limited to situations of acute ingestion, but may also occur due to drug interactions or due to physiological circumstances that impact serum albumin (ie. kidney disease) or drug metabolism.3 Other changes that may result in phenytoin toxicity include pregnancy, malnutrition and malignancy.3

Phenytoin toxicity most often affects the cardiovascular and nervous systems.3 The most common presentation of toxicity depends on the route of administration.3 Cardiovascular adverse effects are most commonly linked to intravenous phenytoin administration, whereas neurological adverse effects are more common with oral phenytoin administration.3

Neurotoxicity is usually dependent on serum concentrations.3 When concentrations range from 10-20 mg/L, mild nystagmus and lateral gaze may occur, while more significant nystagmus is associated with concentrations ranging from 20-30 mg/L.3 At concentrations of 30-40 mg/L, slurred speech, tremor, nausea, vomiting and ataxia have been reported.3 In more serious cases where serum levels range from 40-50 mg/L patients are at risk of lethargy, confusion and hyperactivity, and at levels beyond 50 mg/L, coma and seizures may occur.3

Phenytoin is classified as an antiarrhythmic and can cause SA and AV nodal blocks as well as dysrhythmias due to its effect on voltage-gated sodium channels.3 Further, since phenytoin is poorly soluble, the parenteral form is administered with propylene glycol, which is a cardiac depressant.3 The infusion rate of parenteral phenytoin should not exceed 50 mg per minute due to the risk of hypotension, bradycardia, and asystole.3

Treatment for phenytoin toxicity is non-specific and centres around supportive care.3 One dose of activated charcoal may be used to prevent phenytoin absorption in cases of acute ingestion.3

Although hemodialysis is moderately effective at removing phenytoin, it is not normally recommended due to the risks associated with the procedure, and the general effectiveness of supportive care.3

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Phenytoin (Antiarrhythmic) Action PathwayDrug action
Fosphenytoin (Antiarrhythmic) Action PathwayDrug action
Fosphenytoin (Antiarrhythmic) Metabolism PathwayDrug metabolism
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Cytochrome P450 2C9CYP2C9*3(C;C) / (A;C)C AlleleEffect Directly StudiedPatients with this genotype have reduced metabolism of phenytoin.Details
HLA class I histocompatibility antigen, B-15 alpha chainHLA-B*15:02Not AvailableHLA-B*15ADR Directly StudiedThe presence of this genotype in HLA-B is associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis when treated with phenytoin.Details
Cytochrome P450 2C19CYP2C19*2ANot Available681G>AADR InferredPoor drug metabolizer, risk of drug toxicity.Details
Cytochrome P450 2C19CYP2C19*2BNot Available681G>AADR InferredPoor drug metabolizer, risk of drug toxicity.Details
Cytochrome P450 2C19CYP2C19*3Not Available636G>AADR InferredPoor drug metabolizer, risk of drug toxicity.Details
Cytochrome P450 2C19CYP2C19*4Not Available1A>GADR InferredPoor drug metabolizer, risk of drug toxicity.Details
Cytochrome P450 2C19CYP2C19*5Not Available1297C>TADR InferredPoor drug metabolizer, risk of drug toxicity.Details
Cytochrome P450 2C19CYP2C19*6Not Available395G>AADR InferredPoor drug metabolizer, risk of drug toxicity.Details
Cytochrome P450 2C19CYP2C19*7Not Available19294T>AADR InferredPoor drug metabolizer, risk of drug toxicity.Details
Cytochrome P450 2C19CYP2C19*22Not Available557G>C / 991A>GADR InferredPoor drug metabolizer, risk of drug toxicity.Details
Cytochrome P450 2C19CYP2C19*24Not Available99C>T / 991A>G  … show all ADR InferredPoor drug metabolizer, risk of drug toxicity.Details
Cytochrome P450 2C19CYP2C19*35Not Available12662A>GADR InferredPoor drug metabolizer, risk of drug toxicity.Details
Cytochrome P450 2C9CYP2C9*2Not Available430C>TADR InferredPoor drug metabolizer, risk of drug toxicity. Consider lower dose.Details
Cytochrome P450 2C9CYP2C9*3Not Available1075A>CADR InferredPoor drug metabolizer, risk of drug toxicity. Consider lower dose.Details
Cytochrome P450 2C9CYP2C9*4Not Available1076T>CADR InferredPoor drug metabolizer, risk of drug toxicity. Consider lower dose.Details
Cytochrome P450 2C9CYP2C9*5Not Available1080C>GADR InferredPoor drug metabolizer, risk of drug toxicity. Consider lower dose.Details
Cytochrome P450 2C9CYP2C9*8Not Available449G>AADR InferredPoor drug metabolizer, risk of drug toxicity. Consider lower dose.Details
Cytochrome P450 2C9CYP2C9*11Not Available1003C>TADR InferredPoor drug metabolizer, risk of drug toxicity. Consider lower dose.Details
Cytochrome P450 2C9CYP2C9*12Not Available1465C>TADR InferredPoor drug metabolizer, risk of drug toxicity. Consider lower dose.Details
Cytochrome P450 2C9CYP2C9*13Not Available269T>CADR InferredPoor drug metabolizer, risk of drug toxicity. Consider lower dose.Details
Cytochrome P450 2C9CYP2C9*14Not Available374G>AADR InferredPoor drug metabolizer, risk of drug toxicity. Consider lower dose.Details
Cytochrome P450 2C9CYP2C9*16Not Available895A>GADR InferredPoor drug metabolizer, risk of drug toxicity. Consider lower dose.Details
Cytochrome P450 2C9CYP2C9*18Not Available1075A>C / 1190A>C  … show all ADR InferredPoor drug metabolizer, risk of drug toxicity. Consider lower dose.Details
Cytochrome P450 2C9CYP2C9*26Not Available389C>GADR InferredPoor drug metabolizer, risk of drug toxicity. Consider lower dose.Details
Cytochrome P450 2C9CYP2C9*28Not Available641A>TADR InferredPoor drug metabolizer, risk of drug toxicity. Consider lower dose.Details
Cytochrome P450 2C9CYP2C9*30Not Available1429G>AADR InferredPoor drug metabolizer, risk of drug toxicity. Consider lower dose.Details
Cytochrome P450 2C9CYP2C9*33Not Available395G>AADR InferredPoor drug metabolizer, risk of drug toxicity. Consider lower dose.Details
Cytochrome P450 2C9CYP2C9*6Not Available818delAADR InferredPoor drug metabolizer, risk of drug toxicity. Consider lower dose.Details
Cytochrome P450 2C9CYP2C9*15Not Available485C>AADR InferredPoor drug metabolizer, risk of drug toxicity. Consider lower dose.Details
Cytochrome P450 2C9CYP2C9*25Not Available353_362delAGAAATGGAAADR InferredPoor drug metabolizer, risk of drug toxicity. Consider lower dose.Details
Cytochrome P450 2C9CYP2C9*35Not Available374G>T / 430C>TADR InferredPoor drug metabolizer, risk of drug toxicity. Consider lower dose.Details
Cytochrome P450 2C9CYP2C9*6Not Available818delAEffect InferredPoor drug metabolizer, lower dose requirementsDetails
Cytochrome P450 2C9CYP2C9*15Not Available485C>AEffect InferredPoor drug metabolizer, lower dose requirementsDetails
Cytochrome P450 2C9CYP2C9*25Not Available353_362delAGAAATGGAAEffect InferredPoor drug metabolizer, lower dose requirementsDetails
Cytochrome P450 2C9CYP2C9*35Not Available374G>T / 430C>TEffect InferredPoor drug metabolizer, lower dose requirementsDetails
Cytochrome P450 2C9CYP2C9*2Not Available430C>TEffect InferredPoor drug metabolizer, lower dose requirementsDetails
Cytochrome P450 2C9CYP2C9*4Not Available1076T>CEffect InferredPoor drug metabolizer, lower dose requirementsDetails
Cytochrome P450 2C9CYP2C9*5Not Available1080C>GEffect InferredPoor drug metabolizer, lower dose requirementsDetails
Cytochrome P450 2C9CYP2C9*8Not Available449G>AEffect InferredPoor drug metabolizer, lower dose requirementsDetails
Cytochrome P450 2C9CYP2C9*11Not Available1003C>TEffect InferredPoor drug metabolizer, lower dose requirementsDetails
Cytochrome P450 2C9CYP2C9*12Not Available1465C>TEffect InferredPoor drug metabolizer, lower dose requirementsDetails
Cytochrome P450 2C9CYP2C9*13Not Available269T>CEffect InferredPoor drug metabolizer, lower dose requirementsDetails
Cytochrome P450 2C9CYP2C9*14Not Available374G>AEffect InferredPoor drug metabolizer, lower dose requirementsDetails
Cytochrome P450 2C9CYP2C9*16Not Available895A>GEffect InferredPoor drug metabolizer, lower dose requirementsDetails
Cytochrome P450 2C9CYP2C9*18Not Available1075A>C / 1190A>C  … show all Effect InferredPoor drug metabolizer, lower dose requirementsDetails
Cytochrome P450 2C9CYP2C9*26Not Available389C>GEffect InferredPoor drug metabolizer, lower dose requirementsDetails
Cytochrome P450 2C9CYP2C9*28Not Available641A>TEffect InferredPoor drug metabolizer, lower dose requirementsDetails
Cytochrome P450 2C9CYP2C9*30Not Available1429G>AEffect InferredPoor drug metabolizer, lower dose requirementsDetails
Cytochrome P450 2C9CYP2C9*33Not Available395G>AEffect InferredPoor drug metabolizer, lower dose requirementsDetails

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirThe metabolism of Abacavir can be increased when combined with Phenytoin.
AbametapirThe serum concentration of Phenytoin can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Phenytoin can be increased when combined with Abatacept.
AbirateroneThe metabolism of Abiraterone can be increased when combined with Phenytoin.
AcalabrutinibThe metabolism of Phenytoin can be increased when combined with Acalabrutinib.
AcebutololThe metabolism of Phenytoin can be decreased when combined with Acebutolol.
AceclofenacThe serum concentration of Phenytoin can be increased when it is combined with Aceclofenac.
AcemetacinThe serum concentration of Phenytoin can be increased when it is combined with Acemetacin.
AcenocoumarolThe metabolism of Acenocoumarol can be increased when combined with Phenytoin.
AcetaminophenAcetaminophen may increase the hepatotoxic activities of Phenytoin.
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  • Action
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Food Interactions
  • Avoid alcohol. Alcohol may increase or decrease serum levels of phenytoin.
  • Take separate from antacids. Take at least 2 hours before or after antacids. Taking this medication with antacids can reduce absorption.
  • Take with food. Food reduces irritation and increases bioavailability.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Phenytoin sodium4182431BJH630-93-3FJPYVLNWWICYDW-UHFFFAOYSA-M
Product Images
International/Other Brands
Epanutin ( Pfizer) / Eptoin
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DilantinInjection50 mg/1mLParenteralParke Davis Div Of Pfizer Inc2011-12-302012-01-10US flag
DilantinCapsule100 mgOralUpjohn Canada Ulc1951-12-31Not applicableCanada flag
DilantinInjection50 mg/1mLParenteralParke Davis Div Of Pfizer Inc2011-12-302012-01-10US flag
DilantinCapsule30 mgOralUpjohn Canada Ulc1951-12-31Not applicableCanada flag
Dilantin InfatabsTablet50 mgOralUpjohn Canada Ulc1952-12-31Not applicableCanada flag
Dilantin Inj 50mg/mlLiquidIntramuscular; IntravenousParke Davis Division, Warner Lambert Canada Inc.1972-12-311996-09-10Canada flag
Dilantin KapsealsCapsule, extended release30 mg/1OralPARKE-DAVIS2008-09-222008-09-22US flag
Dilantin-125Suspension125 mg/5mLOralParke-Davis Div of Pfizer Inc1953-01-06Not applicableUS flag
Dilantin-125Suspension125 mg/5mLOralPhysicians Total Care, Inc.1953-01-062010-06-30US flag
Dilantin-125 SuspensionSuspensionOralUpjohn Canada Ulc1953-12-31Not applicableCanada flag
Additional Data Available
  • Application Number
    Application Number
    Available for Purchase

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code
    Available for Purchase

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Apo-phenytoin SodiumCapsuleOralApotex Corporation2017-08-16Not applicableCanada flag
DilantinCapsule100 mg/1OralRemedy Repack2010-03-252017-03-16US flag00071 0369 24 nlmimage10 e51572cb
DilantinCapsule100 mg/1OralParke-Davis Div of Pfizer Inc1976-08-27Not applicableUS flag0071 036920180814 13942 tt9u4a
DilantinCapsule, extended release100 mg/1OralAphena Pharma Solutions Tennessee, Inc.1976-08-27Not applicableUS flag
DilantinCapsule, extended release30 mg/1OralKAISER FOUNDATION HOSPITALS2009-09-202014-12-31US flag
DilantinCapsule, extended release100 mg/1OralA-S Medication Solutions1976-08-27Not applicableUS flag50090 002920180913 8702 104rswg
DilantinCapsule, extended release100 mg/1OralCardinal Health1976-08-272017-05-31US flag55154 242920180907 15195 hrs0b5
DilantinCapsule, extended release100 mg/1OralPhysicians Total Care, Inc.1995-01-27Not applicableUS flag54868 032520180907 15195 1gx7vk3
DilantinCapsule, extended release30 mg/1OralRemedy Repack2009-12-032011-02-01US flag
DilantinCapsule, extended release100 mg/1OralA S Medication Solutions1976-08-27Not applicableUS flag54569 016120180907 15195 f1whrn
Additional Data Available
  • Application Number
    Application Number
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    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code
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Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Dilantin W Phenobarbital 15mgPhenytoin sodium (100 mg) + Phenobarbital (15 mg)CapsuleOralParke Davis Division, Warner Lambert Canada Inc.1951-12-311999-04-08Canada flag
Dilantin W Phenobarbital 30mg CapPhenytoin sodium (100 mg) + Phenobarbital (30 mg)CapsuleOralParke Davis Division, Warner Lambert Canada Inc.1969-12-311997-08-25Canada flag

Categories

ATC Codes
N03AB02 — PhenytoinN03AB52 — Phenytoin, combinations
Drug Categories
Chemical TaxonomyProvided by Classyfire
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
Diphenylmethanes / Phenylimidazolidines / Alpha amino acids and derivatives / 5-monosubstituted hydantoins / N-acyl ureas / Dicarboximides / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organic oxides
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Substituents
5-monosubstituted hydantoin / 5-phenylhydantoin / Alpha-amino acid or derivatives / Aromatic heteromonocyclic compound / Azacycle / Benzenoid / Carbonic acid derivative / Carbonyl group / Carboxylic acid derivative / Dicarboximide
show 13 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
imidazolidine-2,4-dione (CHEBI:8107)

Chemical Identifiers

UNII
6158TKW0C5
CAS number
57-41-0
InChI Key
CXOFVDLJLONNDW-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

References

Synthesis Reference

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

US4642316
General References
  1. Mallet L, Spinewine A, Huang A: The challenge of managing drug interactions in elderly people. Lancet. 2007 Jul 14;370(9582):185-191. doi: 10.1016/S0140-6736(07)61092-7. [PubMed:17630042]
  2. Fischer JH, Patel TV, Fischer PA: Fosphenytoin: clinical pharmacokinetics and comparative advantages in the acute treatment of seizures. Clin Pharmacokinet. 2003;42(1):33-58. doi: 10.2165/00003088-200342010-00002. [PubMed:12489978]
  3. Iorga A, Horowitz BZ: Phenytoin Toxicity . [PubMed:29494051]
  4. Richens A: Clinical pharmacokinetics of phenytoin. Clin Pharmacokinet. 1979 May-Jun;4(3):153-69. doi: 10.2165/00003088-197904030-00001. [PubMed:383353]
  5. Dagenais R, Wilby KJ, Elewa H, Ensom MHH: Impact of Genetic Polymorphisms on Phenytoin Pharmacokinetics and Clinical Outcomes in the Middle East and North Africa Region. Drugs R D. 2017 Sep;17(3):341-361. doi: 10.1007/s40268-017-0195-7. [PubMed:28748348]
  6. Silvado CE, Terra VC, Twardowschy CA: CYP2C9 polymorphisms in epilepsy: influence on phenytoin treatment. Pharmgenomics Pers Med. 2018 Mar 29;11:51-58. doi: 10.2147/PGPM.S108113. eCollection 2018. [PubMed:29636628]
  7. Keppel Hesselink JM: Phenytoin: a step by step insight into its multiple mechanisms of action-80 years of mechanistic studies in neuropharmacology. J Neurol. 2017 Sep;264(9):2043-2047. doi: 10.1007/s00415-017-8465-4. Epub 2017 Mar 27. [PubMed:28349209]
  8. Gupta M, Tripp J: Phenytoin . [PubMed:31855364]
  9. Abdelsayed M, Sokolov S: Voltage-gated sodium channels: pharmaceutical targets via anticonvulsants to treat epileptic syndromes. Channels (Austin). 2013 May-Jun;7(3):146-52. doi: 10.4161/chan.24380. Epub 2013 Mar 26. [PubMed:23531742]
  10. Nation RL, Evans AM, Milne RW: Pharmacokinetic drug interactions with phenytoin (Part I). Clin Pharmacokinet. 1990 Jan;18(1):37-60. [PubMed:2178849]
  11. Bergen DC: Pharmacokinetics of phenytoin: reminders and discoveries. Epilepsy Curr. 2009 Jul-Aug;9(4):102-4. doi: 10.1111/j.1535-7511.2009.01307.x. [PubMed:19693326]
  12. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [PubMed:22569204]
  13. Kinobe RT, Parkinson OT, Mitchell DJ, Gillam EM: P450 2C18 catalyzes the metabolic bioactivation of phenytoin. Chem Res Toxicol. 2005 Dec;18(12):1868-75. doi: 10.1021/tx050181o. [PubMed:16359177]
  14. FDA Approved Drugs: Dilantin [Link]
  15. CEREBYX® FDA Label [Link]
  16. Dilantin® FDA Label (injectable formulation) [Link]
  17. Phenytoin: A Guide to Therapeutic Drug Monitoring [Link]
Human Metabolome Database
HMDB0014397
KEGG Drug
D00512
KEGG Compound
C07443
PubChem Compound
1775
PubChem Substance
46508847
ChemSpider
1710
BindingDB
50003655
RxNav
8183
ChEBI
8107
ChEMBL
CHEMBL16
ZINC
ZINC000002510358
Therapeutic Targets Database
DAP000130
PharmGKB
PA450947
Guide to Pharmacology
GtP Drug Page
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Phenytoin
AHFS Codes
  • 28:12.12 — Hydantoins
MSDS
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Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedOtherCognitive Impairments1
4CompletedOtherCognitive Measures / Driving Simulator Performance1
4CompletedTreatmentAcute Kidney Injury (AKI) / Impaired kidney function / Pharmacokinetics / Renal Failure1
4CompletedTreatmentBronchial Asthma1
4CompletedTreatmentDepression1
4CompletedTreatmentGrand mal Generalized tonic-clonic seizure1
4CompletedTreatmentSubarachnoid Hemorrhage / Traumatic Brain Injury (TBI)1
4RecruitingTreatmentComparison / Management of Pediatric Status Epilepticus / Phenytoin / The Efficacy of Levetireacetam1
4TerminatedTreatmentEpilepsies1
4TerminatedTreatmentSeizures2

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
  • Actavis Group
  • Amerisource Health Services Corp.
  • Amneal Pharmaceuticals
  • Apotheca Inc.
  • A-S Medication Solutions LLC
  • Barr Pharmaceuticals
  • Baxter International Inc.
  • Bilcare Inc.
  • Bryant Ranch Prepack
  • C.O. Truxton Inc.
  • Caraco Pharmaceutical Labs
  • Cardinal Health
  • Carlisle Laboratories Inc.
  • Comprehensive Consultant Services Inc.
  • Coupler Enterprises Inc.
  • Direct Dispensing Inc.
  • Dispensing Solutions
  • Diversified Healthcare Services Inc.
  • General Injectables and Vaccines Inc.
  • Heartland Repack Services LLC
  • Hikma Pharmaceuticals
  • Hospira Inc.
  • JHP Pharmaceuticals LLC
  • Kaiser Foundation Hospital
  • Lake Erie Medical and Surgical Supply
  • Major Pharmaceuticals
  • Medisca Inc.
  • Murfreesboro Pharmaceutical Nursing Supply
  • Mylan
  • Neuman Distributors Inc.
  • Nucare Pharmaceuticals Inc.
  • Palmetto Pharmaceuticals Inc.
  • PCA LLC
  • PD-Rx Pharmaceuticals Inc.
  • Pfizer Inc.
  • Pharmaceutical Packaging Center
  • Pharmedix
  • Physicians Total Care Inc.
  • Prasco Labs
  • Precision Dose Inc.
  • Preferred Pharmaceuticals Inc.
  • Prepackage Specialists
  • Prepak Systems Inc.
  • Rebel Distributors Corp.
  • Redpharm Drug
  • Remedy Repack
  • Resource Optimization and Innovation LLC
  • Sandhills Packaging Inc.
  • Southwood Pharmaceuticals
  • Spectrum Pharmaceuticals
  • Stat Rx Usa
  • Sun Pharmaceutical Industries Ltd.
  • Taro Pharmaceuticals USA
  • Tya Pharmaceuticals
  • UDL Laboratories
  • Vangard Labs Inc.
  • Vistapharm Inc.
  • Warner Chilcott Co. Inc.
  • Warner Lambert Company LLC
  • West-Ward Pharmaceuticals
  • Wockhardt Ltd.
  • Xactdose Inc.
Dosage Forms
FormRouteStrength
Injection, solutionParenteral250 MG/5ML
CapsuleOral30 MG
CapsuleOral30 mg/1
Capsule, extended releaseOral30 mg/1
InjectionParenteral50 mg/1mL
CapsuleOral
Tablet, chewableOral50 mg
TabletOral50 mg
Tablet, chewableOral50 mg/1
SuspensionOral
CapsuleOral
Tablet, coatedOral100 MG
Injection, solution250 mg/5mL
SuspensionOral2.5 g
Capsule, extended releaseOral100 mg
CapsuleOral100 mg
InjectionParenteral250 mg/5ml
Injection, solutionIntramuscular; Intravenous250 mg/5ml
Capsule, coatedOral100 mg
SolutionIntramuscular; Intravenous250 mg
Injection, solutionParenteral50 MG/ML
SolutionIntravenous100 mg
Injection, solution100 mg/2mL
SolutionIntravenous250 mg
Injection
TabletOral100 mg
Capsule, extended releaseOral300 mg/1
SuspensionOral10 mg/1mL
SuspensionOral100 mg/4mL
SuspensionOral125 mg/5mL
Syrup10 mg/1mL
CapsuleOral100 mg/1
Tablet, film coatedOral
Capsule, extended releaseOral100 mg/1
Capsule, extended releaseOral200 mg/1
InjectionIntramuscular; Intravenous250 mg/5mL
InjectionIntramuscular; Intravenous50 mg/1mL
InjectionIntravenous50 mg/1mL
Injection, solutionIntramuscular; Intravenous50 mg/1mL
LiquidIntramuscular; Intravenous
SolutionIntramuscular; Intravenous
Injection, solutionIntramuscular; Intravenous50 mg/ml
Injection250 mg/5ml
Prices
Unit descriptionCostUnit
Dilantin 125 mg/5ml Suspension 237ml Bottle69.28USD bottle
Phenytoin Sodium 50 mg/ml2.64USD ml
Phenytek 300 mg capsule1.47USD capsule
Phenytoin sod ext 300 mg capsule1.2USD capsule
Phenytoin sodium powder1.16USD g
Phenytek 200 mg capsule0.98USD capsule
Phenytoin 50 mg/ml ampul0.96USD ml
Phenytoin sod ext 200 mg capsule0.8USD capsule
Phenytoin 50 mg/ml vial0.67USD ml
Phenytoin 100 mg/2 ml vial0.6USD ml
Dilantin Infatabs 50 mg Chew Tabs0.6USD tab
Dilantin 100 mg capsule0.51USD capsule
Phenytoin 100 mg/4 ml susp0.48USD ml
Dilantin 30 mg capsule0.46USD capsule
Phenytoin 250 mg/5 ml vial0.45USD ml
Dilantin 50 mg infatab0.44USD each
Dilantin 100 mg kapseal0.39USD each
Dilantin 30 mg kapseal0.39USD each
Phenytoin Sodium Extended 100 mg capsule0.36USD capsule
Phenytoin sod ext 100 mg capsule0.34USD capsule
Phenytoin powder0.23USD g
Phenytoin 125 mg/5ml Suspension0.15USD ml
Dilantin Infatabs 50 mg Chewable Tablet0.08USD tablet
Dilantin 100 mg Capsule0.08USD capsule
Dilantin 30 mg Capsule0.06USD capsule
Dilantin-125 25 mg/ml Suspension0.05USD ml
Dilantin-30 6 mg/ml Suspension0.04USD ml
Taro-Phenytoin 25 mg/ml Suspension0.03USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)295 °CMSDS
water solubilityInsoluble in cold waterMSDS
logP2.47HANSCH,C ET AL. (1995)
Caco2 permeability-4.57ADME Research, USCD
pKa8.33SANGSTER (1994)
Predicted Properties
PropertyValueSource
Water Solubility0.0711 mg/mLALOGPS
logP2.26ALOGPS
logP2.15ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)9.47ChemAxon
pKa (Strongest Basic)-9ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area58.2 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity70.18 m3·mol-1ChemAxon
Polarizability25.48 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9909
Blood Brain Barrier+0.976
Caco-2 permeable+0.8867
P-glycoprotein substrateNon-substrate0.5593
P-glycoprotein inhibitor INon-inhibitor0.8782
P-glycoprotein inhibitor IINon-inhibitor0.987
Renal organic cation transporterNon-inhibitor0.8995
CYP450 2C9 substrateNon-substrate0.733
CYP450 2D6 substrateSubstrate0.8911
CYP450 3A4 substrateNon-substrate0.7591
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.8304
CYP450 2D6 inhibitorNon-inhibitor0.935
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8994
Ames testNon AMES toxic0.9132
CarcinogenicityNon-carcinogens0.855
BiodegradationNot ready biodegradable0.992
Rat acute toxicity2.1567 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9793
hERG inhibition (predictor II)Non-inhibitor0.8916
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (9.46 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - EI-BGC-MSsplash10-003r-7930000000-447969b9c242748dd943
GC-MS Spectrum - CI-BGC-MSsplash10-0udi-0090000000-4176043a7a73caee2667
GC-MS Spectrum - EI-BGC-MSsplash10-0zgi-5960000000-e1dcb47a1c082f04f456
GC-MS Spectrum - CI-BGC-MSsplash10-0udi-1390000000-22c71a7e4dbf9c7acab5
GC-MS Spectrum - CI-BGC-MSsplash10-0udi-2190000000-50174e33af92b04d1a6e
Mass Spectrum (Electron Ionization)MSsplash10-0f89-4940000000-2a0dda513d9f63dc6610
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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-0udi-0090000000-aaae845342f345f89695
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-0udi-0390000000-f8da1896c569c120faa2
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-0udi-0920000000-07c872b05aade63c402b
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-0udi-0900000000-be6790637be99260525e
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-0udi-0900000000-9a17fa0b243c8282f3ba
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-0udi-0900000000-69302626996b2b24c153
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0fai-0690000000-f9eeceb82d117127f6ea
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-001i-0910000000-9edcfc62014a6aa7778f
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-001i-0900000000-d4dde5db680fb7722a49
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0ue9-0900000000-482874b33812389ae726
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0udi-0900000000-44f07dc29daf8cdf80c2
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0udi-1900000000-1241292d531ed37544c7
MS/MS Spectrum - , positiveLC-MS/MSsplash10-001i-0950000000-a80521d4dc3976a29b2c
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0ue9-2900000000-a58471ae75fa7319c03d
1H NMR Spectrum1D NMRNot Applicable
13C NMR Spectrum1D NMRNot Applicable

Targets

Kind
Protein
Organism
Humans
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. Mitiushin VM, Kozyreva EV: [Several types of mitochondrial ultrastructure in animal cell mitochondria and their relationship to energy production]. Tsitologiia. 1978 Apr;20(4):371-9. [PubMed:150666]
  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. Yang M, Kozminski DJ, Wold LA, Modak R, Calhoun JD, Isom LL, Brackenbury WJ: Therapeutic potential for phenytoin: targeting Na(v)1.5 sodium channels to reduce migration and invasion in metastatic breast cancer. Breast Cancer Res Treat. 2012 Jul;134(2):603-15. doi: 10.1007/s10549-012-2102-9. Epub 2012 Jun 8. [PubMed:22678159]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated sodium channel activity
Specific Function
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...
Gene Name
SCN1A
Uniprot ID
P35498
Uniprot Name
Sodium channel protein type 1 subunit alpha
Molecular Weight
228969.49 Da
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:15805193]
  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):721-6. [PubMed:17001291]
  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. doi: 10.1016/S1474-4422(10)70059-4. [PubMed:20298965]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Curator comments
weak 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. Faucette SR, Wang H, Hamilton GA, Jolley SL, Gilbert D, Lindley C, Yan B, Negishi M, LeCluyse EL: Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Drug Metab Dispos. 2004 Mar;32(3):348-58. [PubMed:14977870]
  2. 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]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Voltage-gated sodium channel activity involved in purkinje myocyte action potential
Specific Function
Crucial in the assembly, expression, and functional modulation of the heterotrimeric complex of the sodium channel. The subunit beta-1 can modulate multiple alpha subunit isoforms from brain, skele...
Gene Name
SCN1B
Uniprot ID
Q07699
Uniprot Name
Sodium channel subunit beta-1
Molecular Weight
24706.955 Da
References
  1. Lucas PT, Meadows LS, Nicholls J, Ragsdale DS: An epilepsy mutation in the beta1 subunit of the voltage-gated sodium channel results in reduced channel sensitivity to phenytoin. Epilepsy Res. 2005 May;64(3):77-84. [PubMed:15922564]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Voltage-gated sodium channel activity
Specific Function
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...
Gene Name
SCN3A
Uniprot ID
Q9NY46
Uniprot Name
Sodium channel protein type 3 subunit alpha
Molecular Weight
226291.905 Da
References
  1. Lucas PT, Meadows LS, Nicholls J, Ragsdale DS: An epilepsy mutation in the beta1 subunit of the voltage-gated sodium channel results in reduced channel sensitivity to phenytoin. Epilepsy Res. 2005 May;64(3):77-84. [PubMed:15922564]
  2. 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:15805193]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function
Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the ...
Gene Name
KCNH2
Uniprot ID
Q12809
Uniprot Name
Potassium voltage-gated channel subfamily H member 2
Molecular Weight
126653.52 Da
References
  1. Yang M, Kozminski DJ, Wold LA, Modak R, Calhoun JD, Isom LL, Brackenbury WJ: Therapeutic potential for phenytoin: targeting Na(v)1.5 sodium channels to reduce migration and invasion in metastatic breast cancer. Breast Cancer Res Treat. 2012 Jul;134(2):603-15. doi: 10.1007/s10549-012-2102-9. Epub 2012 Jun 8. [PubMed:22678159]
Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
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...

Components:
References
  1. Keppel Hesselink JM: Phenytoin: a step by step insight into its multiple mechanisms of action-80 years of mechanistic studies in neuropharmacology. J Neurol. 2017 Sep;264(9):2043-2047. doi: 10.1007/s00415-017-8465-4. Epub 2017 Mar 27. [PubMed:28349209]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated sodium channel activity
Specific Function
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...
Gene Name
SCN2A
Uniprot ID
Q99250
Uniprot Name
Sodium channel protein type 2 subunit alpha
Molecular Weight
227972.64 Da
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:15805193]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated sodium channel activity
Specific Function
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...
Gene Name
SCN8A
Uniprot ID
Q9UQD0
Uniprot Name
Sodium channel protein type 8 subunit alpha
Molecular Weight
225278.005 Da
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:15805193]
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
General Function
Inhibitory extracellular ligand-gated ion channel activity
Specific Function
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine...

Components:
References
  1. Keppel Hesselink JM: Phenytoin: a step by step insight into its multiple mechanisms of action-80 years of mechanistic studies in neuropharmacology. J Neurol. 2017 Sep;264(9):2043-2047. doi: 10.1007/s00415-017-8465-4. Epub 2017 Mar 27. [PubMed:28349209]

Enzymes

Details
1. Cytochrome P450 2C9
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Substrate
Inhibitor
Inducer
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. Levy RH: Cytochrome P450 isozymes and antiepileptic drug interactions. Epilepsia. 1995;36 Suppl 5:S8-13. [PubMed:8806399]
  2. 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:15805193]
  3. 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:11038165]
  4. Lynch T, Price A: The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 2007 Aug 1;76(3):391-6. [PubMed:17708140]
  5. van der Weide J, Steijns LS, van Weelden MJ, de Haan K: The effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirement. Pharmacogenetics. 2001 Jun;11(4):287-91. [PubMed:11434505]
  6. Johannessen SI, Landmark CJ: Antiepileptic drug interactions - principles and clinical implications. Curr Neuropharmacol. 2010 Sep;8(3):254-67. doi: 10.2174/157015910792246254. [PubMed:21358975]
  7. Flockhart Table of Drug Interactions [Link]
  8. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  9. Get to Know an Enzyme: CYP2C9 [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inducer
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. Levy RH: Cytochrome P450 isozymes and antiepileptic drug interactions. Epilepsia. 1995;36 Suppl 5:S8-13. [PubMed:8806399]
  2. 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:11038165]
  3. Giancarlo GM, Venkatakrishnan K, Granda BW, von Moltke LL, Greenblatt DJ: Relative contributions of CYP2C9 and 2C19 to phenytoin 4-hydroxylation in vitro: inhibition by sulfaphenazole, omeprazole, and ticlopidine. Eur J Clin Pharmacol. 2001 Apr;57(1):31-6. [PubMed:11372587]
  4. Flockhart Table of Drug Interactions [Link]
  5. Cytochrome P450 2C19 by Straight Healthcare [Link]
  6. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inducer
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. Rendic S: Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448. [PubMed:11996015]
  2. Backman JT, Filppula AM, Niemi M, Neuvonen PJ: Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions. Pharmacol Rev. 2016 Jan;68(1):168-241. doi: 10.1124/pr.115.011411. [PubMed:26721703]
  3. Ferguson SS, Chen Y, LeCluyse EL, Negishi M, Goldstein JA: Human CYP2C8 is transcriptionally regulated by the nuclear receptors constitutive androstane receptor, pregnane X receptor, glucocorticoid receptor, and hepatic nuclear factor 4alpha. Mol Pharmacol. 2005 Sep;68(3):747-57. Epub 2005 Jun 2. [PubMed:15933212]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inducer
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. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [PubMed:22569204]
  2. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Substrate
Inducer
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. Ohno Y, Hisaka A, Ueno M, Suzuki H: General framework for the prediction of oral drug interactions caused by CYP3A4 induction from in vivo information. Clin Pharmacokinet. 2008;47(10):669-80. doi: 10.2165/00003088-200847100-00004. [PubMed:18783297]
  2. Zhou SF: Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Curr Drug Metab. 2008 May;9(4):310-22. [PubMed:18473749]
  3. Purkins L, Wood N, Ghahramani P, Love ER, Eve MD, Fielding A: Coadministration of voriconazole and phenytoin: pharmacokinetic interaction, safety, and toleration. Br J Clin Pharmacol. 2003 Dec;56 Suppl 1:37-44. doi: 10.1046/j.1365-2125.2003.01997.x. [PubMed:14616412]
  4. Zhou SF, Xue CC, Yu XQ, Li C, Wang G: Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther Drug Monit. 2007 Dec;29(6):687-710. doi: 10.1097/FTD.0b013e31815c16f5. [PubMed:18043468]
  5. Hole K, Wollmann BM, Nguyen C, Haslemo T, Molden E: Comparison of CYP3A4-Inducing Capacity of Enzyme-Inducing Antiepileptic Drugs Using 4beta-Hydroxycholesterol as Biomarker. Ther Drug Monit. 2018 Aug;40(4):463-468. doi: 10.1097/FTD.0000000000000518. [PubMed:29649093]
  6. Johannessen SI, Landmark CJ: Antiepileptic drug interactions - principles and clinical implications. Curr Neuropharmacol. 2010 Sep;8(3):254-67. doi: 10.2174/157015910792246254. [PubMed:21358975]
  7. Flockhart Table of Drug Interactions [Link]
  8. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inducer
General Function
Oxygen binding
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
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Usui T, Saitoh Y, Komada F: Induction of CYP3As in HepG2 cells by several drugs. Association between induction of CYP3A4 and expression of glucocorticoid receptor. Biol Pharm Bull. 2003 Apr;26(4):510-7. doi: 10.1248/bpb.26.510. [PubMed:12673034]
  2. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [PubMed:22569204]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inducer
General Function
Oxygen binding
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
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57525.03 Da
References
  1. Usui T, Saitoh Y, Komada F: Induction of CYP3As in HepG2 cells by several drugs. Association between induction of CYP3A4 and expression of glucocorticoid receptor. Biol Pharm Bull. 2003 Apr;26(4):510-7. doi: 10.1248/bpb.26.510. [PubMed:12673034]
  2. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [PubMed:22569204]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid 11-beta-monooxygenase activity
Specific Function
Has steroid 11-beta-hydroxylase activity. In addition to this activity, the 18 or 19-hydroxylation of steroids and the aromatization of androstendione to estrone have also been ascribed to cytochro...
Gene Name
CYP11B1
Uniprot ID
P15538
Uniprot Name
Cytochrome P450 11B1, mitochondrial
Molecular Weight
57572.44 Da
References
  1. Funakoshi M: The effect of phenytoin on the corticoidogenesis in the mitochondria and the endoplasmic reticulum of bovine adrenal cortex. Shika Kiso Igakkai Zasshi. 1989 Feb;31(1):95-101. [PubMed:2519258]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inducer
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
References
  1. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [PubMed:22569204]
  2. Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Protein homodimerization activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 3 lacks trans...
Gene Name
UGT1A6
Uniprot ID
P19224
Uniprot Name
UDP-glucuronosyltransferase 1-6
Molecular Weight
60750.215 Da
References
  1. Kostrubsky SE, Sinclair JF, Strom SC, Wood S, Urda E, Stolz DB, Wen YH, Kulkarni S, Mutlib A: Phenobarbital and phenytoin increased acetaminophen hepatotoxicity due to inhibition of UDP-glucuronosyltransferases in cultured human hepatocytes. Toxicol Sci. 2005 Sep;87(1):146-55. doi: 10.1093/toxsci/kfi211. Epub 2005 Jun 2. [PubMed:15933229]
  2. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [PubMed:22569204]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans...
Gene Name
UGT1A9
Uniprot ID
O60656
Uniprot Name
UDP-glucuronosyltransferase 1-9
Molecular Weight
59940.495 Da
References
  1. Kostrubsky SE, Sinclair JF, Strom SC, Wood S, Urda E, Stolz DB, Wen YH, Kulkarni S, Mutlib A: Phenobarbital and phenytoin increased acetaminophen hepatotoxicity due to inhibition of UDP-glucuronosyltransferases in cultured human hepatocytes. Toxicol Sci. 2005 Sep;87(1):146-55. doi: 10.1093/toxsci/kfi211. Epub 2005 Jun 2. [PubMed:15933229]
  2. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [PubMed:22569204]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inducer
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. Johannessen SI, Landmark CJ: Antiepileptic drug interactions - principles and clinical implications. Curr Neuropharmacol. 2010 Sep;8(3):254-67. doi: 10.2174/157015910792246254. [PubMed:21358975]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Const...
Gene Name
CYP2A6
Uniprot ID
P11509
Uniprot Name
Cytochrome P450 2A6
Molecular Weight
56501.005 Da
References
  1. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [PubMed:22569204]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
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. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [PubMed:22569204]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
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. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [PubMed:22569204]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Substrate
General Function
Biotransformation enzyme that catalyzes the hydrolysis of arene and aliphatic epoxides to less reactive and more water soluble dihydrodiols by the trans addition of water (By similarity). May play a role in the metabolism of endogenous lipids such as epoxide-containing fatty acids (PubMed:22798687).
Specific Function
Cis-stilbene-oxide hydrolase activity
Gene Name
EPHX1
Uniprot ID
P07099
Uniprot Name
Epoxide hydrolase 1
Molecular Weight
52948.48 Da
References
  1. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [PubMed:22569204]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Substrate
General Function
Protein homodimerization activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A4
Uniprot ID
P22310
Uniprot Name
UDP-glucuronosyltransferase 1-4
Molecular Weight
60024.535 Da
References
  1. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [PubMed:22569204]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Substrate
General Function
O-methyltransferase activity
Specific Function
Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like L-DOP...
Gene Name
COMT
Uniprot ID
P21964
Uniprot Name
Catechol O-methyltransferase
Molecular Weight
30036.77 Da
References
  1. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [PubMed:22569204]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Substrate
General Function
Superoxide dismutase activity
Specific Function
The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinons involved in detoxification pathways as well as in biosynthetic processes such as the vit...
Gene Name
NQO1
Uniprot ID
P15559
Uniprot Name
NAD(P)H dehydrogenase [quinone] 1
Molecular Weight
30867.405 Da
References
  1. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [PubMed:22569204]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
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
CYP2C18
Uniprot ID
P33260
Uniprot Name
Cytochrome P450 2C18
Molecular Weight
55710.075 Da
References
  1. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [PubMed:22569204]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
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:15282104]
  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:16621742]
  3. Co M, Lo A: Effect of albumin on phenytoin concentration: are we flogging a dead horse? Can J Hosp Pharm. 2011 Jul;64(4):293. doi: 10.4212/cjhp.v64i4.1051. [PubMed:22479078]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Serine-type endopeptidase inhibitor activity
Specific Function
Major thyroid hormone transport protein in serum.
Gene Name
SERPINA7
Uniprot ID
P05543
Uniprot Name
Thyroxine-binding globulin
Molecular Weight
46324.12 Da
References
  1. Finucane JF, Griffiths RS: Effect of phenytoin therapy on thyroid function. Br J Clin Pharmacol. 1976 Dec;3(6):1041-4. doi: 10.1111/j.1365-2125.1976.tb00355.x. [PubMed:22216527]
  2. EUTHYROX (levothyroxine sodium) tablets, for oral use - FDA Label [Link]
  3. CYTOMEL (liothyronine) FDA label [File]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Thyroid hormone transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent high affinity transport of organic anions such as the thyroid hormones thyroxine (T4) and rT3. Other potential substrates, such as triiodothyronine (T3), 17-beta-gluc...
Gene Name
SLCO1C1
Uniprot ID
Q9NYB5
Uniprot Name
Solute carrier organic anion transporter family member 1C1
Molecular Weight
78695.625 Da
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. doi: 10.1210/en.2008-0188. Epub 2008 Oct 9. [PubMed:18845642]
  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:10592235]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
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:17045309]
  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. doi: 10.1016/j.neuropharm.2008.08.032. Epub 2008 Sep 11. [PubMed:18824002]
  3. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [PubMed:22569204]
  4. Simon C, Stieger B, Kullak-Ublick GA, Fried M, Mueller S, Fritschy JM, Wieser HG, Pauli-Magnus C: Intestinal expression of cytochrome P450 enzymes and ABC transporters and carbamazepine and phenytoin disposition. Acta Neurol Scand. 2007 Apr;115(4):232-42. doi: 10.1111/j.1600-0404.2006.00761.x. [PubMed:17376120]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Organic anion transmembrane transporter activity
Specific Function
Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter.
Gene Name
ABCC2
Uniprot ID
Q92887
Uniprot Name
Canalicular multispecific organic anion transporter 1
Molecular Weight
174205.64 Da
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:17045309]
  2. Potschka H, Fedrowitz M, Loscher W: Multidrug resistance protein MRP2 contributes to blood-brain barrier function and restricts antiepileptic drug activity. J Pharmacol Exp Ther. 2003 Jul;306(1):124-31. doi: 10.1124/jpet.103.049858. Epub 2003 Mar 27. [PubMed:12663688]
  3. Simon C, Stieger B, Kullak-Ublick GA, Fried M, Mueller S, Fritschy JM, Wieser HG, Pauli-Magnus C: Intestinal expression of cytochrome P450 enzymes and ABC transporters and carbamazepine and phenytoin disposition. Acta Neurol Scand. 2007 Apr;115(4):232-42. doi: 10.1111/j.1600-0404.2006.00761.x. [PubMed:17376120]

Drug created on June 13, 2005 07:24 / Updated on October 29, 2020 19:26

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