Phenytoin

Identification

Summary

Phenytoin is an anticonvulsant drug used in the prophylaxis and control of various types of seizures.

Brand Names
Dilantin, Phenytek
Generic Name
Phenytoin
DrugBank Accession Number
DB00252
Background

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
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
  • PR-122 (redox-phenytoin)
  • Redox-phenytoin
External IDs
  • NSC-8722
  • PR-122

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

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofComplex partial seizures•••••••••••••••••••• •••••••• •••••••• ••••••••••
Used in combination to treatGrand mal status epilepticusCombination Product in combination with: Phenobarbital (DB01174), Gamma-amino-beta-hydroxybutyric acid (DB15985)••••••••••••••••••
Used in combination to treatGrand mal generalized tonic-clonic seizureCombination Product in combination with: Methylphenobarbital (DB00849)•••••••••••••••••••••• ••••••• •••• •••••••••••••••••
Treatment ofGrand mal generalized tonic-clonic seizure•••••••••••••••••••• •••••••• •••••••• ••••••••••
Used in combination to treatJacksonian epilepsyCombination Product in combination with: Phenobarbital (DB01174), Gamma-amino-beta-hydroxybutyric acid (DB15985)••••••••••••••••••
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
AVoltage-gated inwardly rectifying potassium channel KCNH2
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
UNuclear receptor subfamily 1 group I member 2Not AvailableHumans
USodium channel regulatory subunit beta-1Not AvailableHumans
USodium channel protein type 3 subunit alphaNot AvailableHumans
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

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
1,2-BenzodiazepineThe metabolism of 1,2-Benzodiazepine can be increased when combined with Phenytoin.
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.
AbemaciclibThe metabolism of Abemaciclib can be increased when combined with Phenytoin.
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 mgOralBgp Pharma Ulc1951-12-31Not applicableCanada flag
DilantinInjection50 mg/1mLParenteralParke-Davis Div of Pfizer Inc2011-12-302012-01-10US flag
DilantinCapsule30 mgOralBgp Pharma Ulc1951-12-31Not applicableCanada flag
Dilantin InfatabsTablet, chewable50 mgOralBgp Pharma Ulc1952-12-31Not applicableCanada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DilantinTablet, chewable50 mg/1OralRemedy Repack2010-08-122013-01-30US flag
DilantinCapsule30 mg/1OralParke-Davis Div of Pfizer Inc1976-08-27Not applicableUS flag
DilantinCapsule100 mg/1OralREMEDYREPACK INC.2024-09-24Not applicableUS flag
DilantinCapsule, extended release30 mg/1OralAvera McKennan Hospital2015-09-14Not applicableUS flag
DilantinCapsule, extended release30 mg/1OralREMEDYREPACK INC.2018-01-22Not applicableUS flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Dilantin W Phenobarbital 15mgPhenytoin sodium (100 mg / cap) + Phenobarbital (15 mg / cap)CapsuleOralParke Davis Division, Warner Lambert Canada Inc.1951-12-311999-04-08Canada flag
Dilantin W Phenobarbital 30mg CapPhenytoin sodium (100 mg / cap) + Phenobarbital (30 mg / cap)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
show 2 more
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)
Affected organisms
  • Humans and other mammals

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. [Article]
  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. [Article]
  3. Iorga A, Horowitz BZ: Phenytoin Toxicity . [Article]
  4. Richens A: Clinical pharmacokinetics of phenytoin. Clin Pharmacokinet. 1979 May-Jun;4(3):153-69. doi: 10.2165/00003088-197904030-00001. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  8. Gupta M, Tripp J: Phenytoin . [Article]
  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. [Article]
  10. Nation RL, Evans AM, Milne RW: Pharmacokinetic drug interactions with phenytoin (Part I). Clin Pharmacokinet. 1990 Jan;18(1):37-60. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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
MSDS
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Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
Not AvailableCompletedNot AvailableAcute Kidney Injury (AKI) / Impaired Renal Function / Kidney Failure / Pharmacokinetics1somestatusstop reasonjust information to hide
Not AvailableCompletedNot AvailableEpilepsy1somestatusstop reasonjust information to hide
Not AvailableCompletedNot AvailableHealthy Volunteers (HV)1somestatusstop reasonjust information to hide
Not AvailableCompletedTreatmentCysticercosis / Epilepsy1somestatusstop reasonjust information to hide
Not AvailableCompletedTreatmentOsteonecrosis Due to Drugs, Jaw1somestatusstop reasonjust information to hide

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
SolutionParenteral250.000 mg
InjectionIntravenous50 mg/ml
CapsuleOral30 mg/1
Capsule, extended releaseOral100.02 mg
Capsule, extended releaseOral30 mg/1
Injection250 MG/ML
Injection250 mg/5ml
InjectionParenteral50 mg/1mL
SuspensionOral125.00 mg/5ml
Tablet, chewableOral50 mg
Tablet, chewableOral50 mg/1
LiquidIntramuscular; Intravenous250 mg / 5 mL
Injection, solutionIntramuscular; Intravenous250 MG/5ML
CapsuleOral
SuspensionOral125 mg / 5 mL
SuspensionOral30 mg / 5 mL
Tablet, coatedOral100 MG
CapsuleOral0.1000 g
SuspensionOral0.750 g
SuspensionOral250000 g
Capsule, coatedOral0.1 g
SuspensionOral0.75 g
SolutionParenteral100 mg
SuspensionOral750 mg
SolutionIntramuscular; Intravenous25000000 mg
InjectionParenteral250 mg/5ml
TabletOral
Injection, solutionIntravenous
SolutionIntravenous250 mg
SolutionIntravenous25000000 mg
TabletOral100.00 mg
Injection, solutionIntramuscular; Intravenous50 mg/ml
Capsule, coatedOral100 mg
SolutionIntramuscular; Intravenous250 mg
Injection, solutionParenteral50 MG/ML
Injection, solution
SolutionIntravenous100 mg
InjectionParenteral50 mg
SuspensionOral2.5 g
SolutionIntramuscular0.25 g
SolutionParenteral250.00 mg
TabletOral
TabletOral100 mg
SolutionIntravenous250.000 mg
InjectionIntravenous
Injection100 MG/2ML
Capsule, extended releaseOral300 mg/1
SuspensionOral100 mg/4mL
SuspensionOral125 mg/5mL
CapsuleOral100 mg/1
Tablet, film coatedOral100 MG
Capsule, extended releaseOral100 mg/1
Capsule, extended releaseOral200 mg/1
Injection50 MG/ML
Injection50 mg/2ml
InjectionIntramuscular; Intravenous250 mg/5mL
InjectionIntramuscular; Intravenous50 mg/1mL
InjectionIntravenous50 mg/1mL
Injection, solutionIntramuscular; Intravenous50 mg/1mL
LiquidIntramuscular; Intravenous50 mg / mL
SolutionIntramuscular; Intravenous50 mg / mL
Injection, solutionIntramuscular; Intravenous
Injection, solution250 mg/5ml
CapsuleOral
CapsuleOral100 mg
Injection, solution50 mg/1ml
TabletOral50 mg
Capsule, extended releaseOral100 mg
CapsuleOral30 mg
Solution50 mg/1ml
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)8.49Chemaxon
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-MSsplash10-00lr-0920000000-edf72a4c297e405a2600
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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSsplash10-001i-0950000000-a80521d4dc3976a29b2c
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSsplash10-0ue9-2900000000-a58471ae75fa7319c03d
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
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0udi-0090000000-2df6f1e897049cb4225a
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0udi-0970000000-d6fa8d45c11aab3cb607
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udi-0090000000-c8a4b96862aaabfe961d
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0udi-1910000000-68db14ca10242042856a
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udl-8090000000-ae505a38e2dfb034dd75
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udl-7900000000-71cfce3a8cdaa2b3cce2
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0udi-0190000000-a6afb7af3208c88f9ab5
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udi-1090000000-39980c35380dc920ca68
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0udi-0940000000-332ca131e5d1a7567fbc
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0f7o-9750000000-d31901c611520cf89dee
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0udi-1900000000-a8d9936c1921908faf45
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0006-9200000000-b82dc5180c73f5be11b4
1H NMR Spectrum1D NMRNot Applicable
13C NMR Spectrum1D NMRNot Applicable
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-165.6064765
predicted
DarkChem Lite v0.1.0
[M-H]-152.72073
predicted
DeepCCS 1.0 (2019)
[M-H]-165.6064765
predicted
DarkChem Lite v0.1.0
[M-H]-152.72073
predicted
DeepCCS 1.0 (2019)
[M+H]+166.2300765
predicted
DarkChem Lite v0.1.0
[M+H]+155.07874
predicted
DeepCCS 1.0 (2019)
[M+H]+166.2300765
predicted
DarkChem Lite v0.1.0
[M+H]+155.07874
predicted
DeepCCS 1.0 (2019)
[M+Na]+166.6967765
predicted
DarkChem Lite v0.1.0
[M+Na]+161.17189
predicted
DeepCCS 1.0 (2019)
[M+Na]+166.6967765
predicted
DarkChem Lite v0.1.0
[M+Na]+161.17189
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Pore-forming subunit of Nav1.5, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes. Navs, also called VGSCs (voltage-gated sodium channels) or VDSCs (voltage-dependent sodium channels), operate by switching between closed and open conformations depending on the voltage difference across the membrane. In the open conformation they allow Na(+) ions to selectively pass through the pore, along their electrochemical gradient. The influx of Na(+) ions provokes membrane depolarization, initiating the propagation of electrical signals throughout cells and tissues (PubMed:1309946, PubMed:21447824, PubMed:23085483, PubMed:23420830, PubMed:25370050, PubMed:26279430, PubMed:26392562, PubMed:26776555). Nav1.5 is the predominant sodium channel expressed in myocardial cells and it is responsible for the initial upstroke of the action potential in cardiac myocytes, thereby initiating the heartbeat (PubMed:11234013, PubMed:11804990, PubMed:12569159, PubMed:1309946). Required for normal electrical conduction including formation of the infranodal ventricular conduction system and normal action potential configuration, as a result of its interaction with XIRP2 (By similarity)
Specific Function
ankyrin binding
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. [Article]
  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. [Article]
  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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General 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 sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient (PubMed:14672992). Plays a key role in brain, probably by regulating the moment when neurotransmitters are released in neurons. Involved in sensory perception of mechanical pain: activation in somatosensory neurons induces pain without neurogenic inflammation and produces hypersensitivity to mechanical, but not thermal stimuli
Specific Function
voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential
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. [Article]
  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. [Article]
  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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel (PubMed:10219239, PubMed:10753933, PubMed:10790218, PubMed:10837251, PubMed:11997281, PubMed:12063277, PubMed:18559421, PubMed:22314138, PubMed:22359612, PubMed:26363003, PubMed:27916661, PubMed:9230439, PubMed:9351446, PubMed:9765245). Channel properties are modulated by cAMP and subunit assembly (PubMed:10837251). Characterized by unusual gating kinetics by producing relatively small outward currents during membrane depolarization and large inward currents during subsequent repolarization which reflect a rapid inactivation during depolarization and quick recovery from inactivation but slow deactivation (closing) during repolarization (PubMed:10219239, PubMed:10753933, PubMed:10790218, PubMed:10837251, PubMed:11997281, PubMed:12063277, PubMed:18559421, PubMed:22314138, PubMed:22359612, PubMed:26363003, PubMed:27916661, PubMed:9230439, PubMed:9351446, PubMed:9765245). Channel properties are modulated by cAMP and subunit assembly (PubMed:10837251). Forms a stable complex with KCNE1 or KCNE2, and that this heteromultimerization regulates inward rectifier potassium channel activity (PubMed:10219239, PubMed:9230439)
Specific Function
delayed rectifier potassium channel activity
Gene Name
KCNH2
Uniprot ID
Q12809
Uniprot Name
Voltage-gated inwardly rectifying potassium channel KCNH2
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. [Article]
Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents (PubMed:11741969, PubMed:12176756, PubMed:12181424, PubMed:15454078, PubMed:15863612, PubMed:16299511, PubMed:17071743, PubMed:17224476, PubMed:20953164, PubMed:23677916, PubMed:24728418, PubMed:26253506, PubMed:27218670, PubMed:29078335, PubMed:29742403, PubMed:30023270, PubMed:30172029, PubMed:34163037, PubMed:7737988, PubMed:8099908, PubMed:8392192, PubMed:9013606, PubMed:9087614, PubMed:9607315). Mediates influx of calcium ions into the cytoplasm, and thereby triggers calcium release from the sarcoplasm (By similarity). Plays an important role in excitation-contraction coupling in the heart. Required for normal heart development and normal regulation of heart rhythm (PubMed:15454078, PubMed:15863612, PubMed:17224476, PubMed:24728418, PubMed:26253506). Required for normal contraction of smooth muscle cells in blood vessels and in the intestine. Essential for normal blood pressure regulation via its role in the contraction of arterial smooth muscle cells (PubMed:28119464). Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group (Probable)
Specific Function
alpha-actinin binding

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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General 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 sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient (PubMed:1325650, PubMed:17021166, PubMed:28256214, PubMed:29844171). Implicated in the regulation of hippocampal replay occurring within sharp wave ripples (SPW-R) important for memory (By similarity)
Specific Function
calmodulin binding
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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Pore-forming subunit of a voltage-gated sodium channel complex assuming opened or closed conformations in response to the voltage difference across membranes and through which sodium ions selectively pass along their electrochemical gradient (PubMed:24874546, PubMed:25239001, PubMed:25725044, PubMed:26900580, PubMed:29726066, PubMed:33245860, PubMed:36696443, PubMed:36823201). Contributes to neuronal excitability by regulating action potential threshold and propagation (PubMed:24874546, PubMed:25239001, PubMed:25725044, PubMed:26900580, PubMed:29726066, PubMed:33245860, PubMed:36696443, PubMed:36823201)
Specific Function
sodium ion binding
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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Curator comments
weak activator
General 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 and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes
Specific Function
DNA-binding transcription activator activity, RNA polymerase II-specific
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. [Article]
  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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Regulatory subunit of multiple voltage-gated sodium (Nav) channels directly mediating the depolarization of excitable membranes. Navs, also called VGSCs (voltage-gated sodium channels) or VDSCs (voltage-dependent sodium channels), operate by switching between closed and open conformations depending on the voltage difference across the membrane. In the open conformation they allow Na(+) ions to selectively pass through the pore, along their electrochemical gradient. The influx of Na+ ions provokes membrane depolarization, initiating the propagation of electrical signals throughout cells and tissues (PubMed:14622265, PubMed:15525788, PubMed:18464934, PubMed:19710327, PubMed:29992740, PubMed:36696443, PubMed:8125980, PubMed:8394762). The accessory beta subunits participate in localization and functional modulation of the Nav channels (PubMed:15525788, PubMed:19710327, PubMed:29992740). Modulates the activity of SCN1A/Nav1.1, SCN2A/Nav1.2, SCN3A/Nav1.3, SCN4A/Nav1.4, SCN5A/Nav1.5, SCN8A/Nav1.6, SCN9A/Nav1.7 and SCN10A/Nav1.8 (PubMed:14622265, PubMed:15525788, PubMed:18464934, PubMed:30765606, PubMed:36696443, PubMed:8125980, PubMed:8394762)
Specific Function
sodium channel inhibitor activity
Gene Name
SCN1B
Uniprot ID
Q07699
Uniprot Name
Sodium channel regulatory 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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Pore-forming subunit of Nav1.3, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes. Navs, also called VGSCs (voltage-gated sodium channels) or VDSCs (voltage-dependent sodium channels), operate by switching between closed and open conformations depending on the voltage difference across the membrane. In the open conformation they allow Na(+) ions to selectively pass through the pore, along their electrochemical gradient. The influx of Na+ ions provokes membrane depolarization, initiating the propagation of electrical signals throughout cells and tissues (PubMed:24157691, PubMed:28235671, PubMed:29466837, PubMed:35277491). In some secretory cell types, it also participates in cell excitability through membrane depolarization and regulates cells responsiveness to stimuli triggering secretion. For instance, it controls the release of serotonin/5-hydroxytryptamine by enterochromaffin cells and is required for both glucagon- and glucose-induced insulin secretion in pancreatic endocrine cells (By similarity)
Specific Function
voltage-gated sodium channel activity
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. [Article]
  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. [Article]
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
General Function
Alpha subunit of the heteropentameric ligand-gated chloride channel gated by Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain (PubMed:23909897, PubMed:25489750, PubMed:29950725, PubMed:30602789). GABA-gated chloride channels, also named GABA(A) receptors (GABAAR), consist of five subunits arranged around a central pore and contain GABA active binding site(s) located at the alpha and beta subunit interface(s) (PubMed:29950725, PubMed:30602789). When activated by GABA, GABAARs selectively allow the flow of chloride anions across the cell membrane down their electrochemical gradient (PubMed:23909897, PubMed:29950725, PubMed:30602789). Alpha-1/GABRA1-containing GABAARs are largely synaptic (By similarity). Chloride influx into the postsynaptic neuron following GABAAR opening decreases the neuron ability to generate a new action potential, thereby reducing nerve transmission (By similarity). GABAARs containing alpha-1 and beta-2 or -3 subunits exhibit synaptogenic activity; the gamma-2 subunit being necessary but not sufficient to induce rapid synaptic contacts formation (PubMed:23909897, PubMed:25489750). GABAARs function also as histamine receptor where histamine binds at the interface of two neighboring beta subunits and potentiates GABA response (By similarity). GABAARs containing alpha, beta and epsilon subunits also permit spontaneous chloride channel activity while preserving the structural information required for GABA-gated openings (By similarity). Alpha-1-mediated plasticity in the orbitofrontal cortex regulates context-dependent action selection (By similarity). Together with rho subunits, may also control neuronal and glial GABAergic transmission in the cerebellum (By similarity)
Specific Function
GABA-A receptor activity

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. [Article]

Enzymes

Details
1. Cytochrome P450 2C9
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
Inducer
General Function
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:15766564, PubMed:19965576, PubMed:7574697, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9435160, PubMed:9866708). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031)
Specific Function
(R)-limonene 6-monooxygenase activity
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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  6. Johannessen SI, Landmark CJ: Antiepileptic drug interactions - principles and clinical implications. Curr Neuropharmacol. 2010 Sep;8(3):254-67. doi: 10.2174/157015910792246254. [Article]
  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
No
Actions
Substrate
Inducer
General Function
A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates PUFA specifically at the omega-1 position (PubMed:18577768). Catalyzes the epoxidation of double bonds of PUFA (PubMed:19965576, PubMed:20972997). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Hydroxylates fenbendazole at the 4' position (PubMed:23959307)
Specific Function
(R)-limonene 6-monooxygenase activity
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55944.565 Da
References
  1. Levy RH: Cytochrome P450 isozymes and antiepileptic drug interactions. Epilepsia. 1995;36 Suppl 5:S8-13. [Article]
  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. [Article]
  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. [Article]
  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
No
Actions
Substrate
Inducer
General Function
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:15766564, PubMed:19965576, PubMed:7574697). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316)
Specific Function
arachidonic acid epoxygenase activity
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. [Article]
  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. [Article]
  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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inducer
General Function
A cytochrome P450 monooxygenase involved in the metabolism of endocannabinoids and steroids (PubMed:12865317, PubMed:21289075). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the epoxidation of double bonds of arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:21289075). Hydroxylates steroid hormones, including testosterone at C-16 and estrogens at C-2 (PubMed:12865317, PubMed:21289075). Plays a role in the oxidative metabolism of xenobiotics, including plant lipids and drugs (PubMed:11695850, PubMed:22909231). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850)
Specific Function
anandamide 11,12 epoxidase activity
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. [Article]
  2. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inducer
General Function
A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
Specific Function
1,8-cineole 2-exo-monooxygenase activity
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. [Article]
  2. Zhou SF: Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Curr Drug Metab. 2008 May;9(4):310-22. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  6. Johannessen SI, Landmark CJ: Antiepileptic drug interactions - principles and clinical implications. Curr Neuropharmacol. 2010 Sep;8(3):254-67. doi: 10.2174/157015910792246254. [Article]
  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
A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and vitamins (PubMed:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). Exhibits high catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes 6beta-hydroxylation of the steroid hormones testosterone, progesterone, and androstenedione (PubMed:2732228). Catalyzes the oxidative conversion of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Also involved in the oxidative metabolism of xenobiotics, including calcium channel blocking drug nifedipine and immunosuppressive drug cyclosporine (PubMed:2732228)
Specific Function
aromatase activity
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. [Article]
  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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inducer
General Function
A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and vitamins during embryogenesis (PubMed:11093772, PubMed:12865317, PubMed:14559847, PubMed:17178770, PubMed:9555064). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:11093772, PubMed:12865317, PubMed:14559847, PubMed:17178770, PubMed:9555064). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes 3beta-hydroxyandrost-5-en-17-one (dehydroepiandrosterone, DHEA), a precursor in the biosynthesis of androgen and estrogen steroid hormones (PubMed:17178770, PubMed:9555064). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1), particularly D-ring hydroxylated estrone at the C16-alpha position (PubMed:12865317, PubMed:14559847). Mainly hydroxylates all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may play a role in atRA clearance during fetal development (PubMed:11093772). Also involved in the oxidative metabolism of xenobiotics including anticonvulsants (PubMed:9555064)
Specific Function
all-trans retinoic acid 18-hydroxylase activity
Gene Name
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57469.95 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. [Article]
  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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
A cytochrome P450 monooxygenase involved in the biosynthesis of adrenal corticoids (PubMed:12530636, PubMed:1518866, PubMed:1775135, PubMed:18215163, PubMed:23322723). Catalyzes a variety of reactions that are essential for many species, including detoxification, defense, and the formation of endogenous chemicals like steroid hormones. Steroid 11beta, 18- and 19-hydroxylase with preferred regioselectivity at 11beta, then 18, and lastly 19 (By similarity). Catalyzes the hydroxylation of 11-deoxycortisol and 11-deoxycorticosterone (21-hydroxyprogesterone) at 11beta position, yielding cortisol or corticosterone, respectively, but cannot produce aldosterone (PubMed:12530636, PubMed:1518866, PubMed:1775135, PubMed:18215163, PubMed:23322723). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate for hydroxylation and reducing the second into a water molecule. Two electrons are provided by NADPH via a two-protein mitochondrial transfer system comprising flavoprotein FDXR (adrenodoxin/ferredoxin reductase) and nonheme iron-sulfur protein FDX1 or FDX2 (adrenodoxin/ferredoxin) (PubMed:18215163). Due to its lack of 18-oxidation activity, it is incapable of generating aldosterone (PubMed:23322723). Could also be involved in the androgen metabolic pathway (Probable)
Specific Function
corticosterone 18-monooxygenase activity
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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inducer
General Function
UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:12181437, PubMed:15472229, PubMed:18004206, PubMed:18004212, PubMed:18719240, PubMed:19830808, PubMed:23288867). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004206, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol, estrone and estriol (PubMed:15472229, PubMed:18719240, PubMed:23288867). Involved in the glucuronidation of bilirubin, a degradation product occurring in the normal catabolic pathway that breaks down heme in vertebrates (PubMed:17187418, PubMed:18004206, PubMed:19830808, PubMed:24525562). Also catalyzes the glucuronidation the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist losartan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:18004212, PubMed:20610558)
Specific Function
enzyme binding
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1A1
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. [Article]
  2. Hirashima R, Michimae H, Takemoto H, Sasaki A, Kobayashi Y, Itoh T, Tukey RH, Fujiwara R: Induction of the UDP-Glucuronosyltransferase 1A1 during the Perinatal Period Can Cause Neurodevelopmental Toxicity. Mol Pharmacol. 2016 Sep;90(3):265-74. doi: 10.1124/mol.116.104174. Epub 2016 Jul 13. [Article]
  3. Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General 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 transferase activity but acts as a negative regulator of isoform 1 (By similarity)
Specific Function
enzyme binding
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. [Article]
  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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:12181437, PubMed:15470161, PubMed:15472229, PubMed:18004212, PubMed:18052087, PubMed:18674515, PubMed:19545173). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol and estrone (PubMed:15472229). Also catalyzes the glucuronidation of the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist caderastan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:20610558). Also metabolizes mycophenolate, an immunosuppressive agent (PubMed:15470161, PubMed:18004212)
Specific Function
enzyme binding
Gene Name
UGT1A9
Uniprot ID
O60656
Uniprot Name
UDP-glucuronosyltransferase 1A9
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. [Article]
  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. [Article]
  3. Yamanaka H, Nakajima M, Hara Y, Katoh M, Tachibana O, Yamashita J, Yokoi T: Urinary excretion of phenytoin metabolites, 5-(4'-hydroxyphenyl)-5-phenylhydantoin and its O-glucuronide in humans and analysis of genetic polymorphisms of UDP-glucuronosyltransferases. Drug Metab Pharmacokinet. 2005 Apr;20(2):135-43. doi: 10.2133/dmpk.20.135. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inducer
General Function
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:11555828, PubMed:12865317). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2 (PubMed:11555828, PubMed:12865317). Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). May act as a major enzyme for all-trans retinoic acid biosynthesis in the liver. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer (PubMed:19965576). Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA (PubMed:9435160). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin (PubMed:14725854). Metabolizes caffeine via N3-demethylation (Probable)
Specific Function
aromatase activity
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58406.915 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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General 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. Constitutes the major nicotine C-oxidase. Acts as a 1,4-cineole 2-exo-monooxygenase. Possesses low phenacetin O-deethylation activity
Specific Function
arachidonic acid epoxygenase activity
Gene Name
CYP2A6
Uniprot ID
P11509
Uniprot Name
Cytochrome P450 2A6
Molecular Weight
56517.005 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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:19965576, PubMed:20972997). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:18698000, PubMed:21289075). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid (PubMed:10681376). Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants
Specific Function
anandamide 11,12 epoxidase activity
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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of fatty acids (PubMed:10553002, PubMed:18577768). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:10553002, PubMed:18577768). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates fatty acids specifically at the omega-1 position displaying the highest catalytic activity for saturated fatty acids (PubMed:10553002, PubMed:18577768). May be involved in the oxidative metabolism of xenobiotics (Probable)
Specific Function
4-nitrophenol 2-monooxygenase activity
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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
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). Plays a role in the metabolism of endogenous lipids such as epoxide-containing fatty acids (PubMed:22798687). Metabolizes the abundant endocannabinoid 2-arachidonoylglycerol (2-AG) to free arachidonic acid (AA) and glycerol (PubMed:24958911). Binds 20(S)-hydroxycholesterol (20(S)-OHC) (By similarity)
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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:18177842, PubMed:24641623). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:18177842). Involved in the glucuronidation of calcidiol, which is the major circulating form of vitamin D3 essential for the regulation of calcium and phosphate homeostasis (PubMed:24641623). Also glucuronidates the biologically active form of vitamin D3, calcitriol, probably leading to its biliary transport and intestinal reabsorption (PubMed:18177842)
Specific Function
enzyme binding
Gene Name
UGT1A4
Uniprot ID
P22310
Uniprot Name
UDP-glucuronosyltransferase 1A4
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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General 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-DOPA, alpha-methyl DOPA and isoproterenol
Specific Function
catechol O-methyltransferase activity
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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Flavin-containing quinone reductase that catalyzes two-electron reduction of quinones to hydroquinones using either NADH or NADPH as electron donors. In a ping-pong kinetic mechanism, the electrons are sequentially transferred from NAD(P)H to flavin cofactor and then from reduced flavin to the quinone, bypassing the formation of semiquinone and reactive oxygen species (By similarity) (PubMed:8999809, PubMed:9271353). Regulates cellular redox state primarily through quinone detoxification. Reduces components of plasma membrane redox system such as coenzyme Q and vitamin quinones, producing antioxidant hydroquinone forms. In the process may function as superoxide scavenger to prevent hydroquinone oxidation and facilitate excretion (PubMed:15102952, PubMed:8999809, PubMed:9271353). Alternatively, can activate quinones and their derivatives by generating redox reactive hydroquinones with DNA cross-linking antitumor potential (PubMed:8999809). Acts as a gatekeeper of the core 20S proteasome known to degrade proteins with unstructured regions. Upon oxidative stress, interacts with tumor suppressors TP53 and TP73 in a NADH-dependent way and inhibits their ubiquitin-independent degradation by the 20S proteasome (PubMed:15687255, PubMed:28291250)
Specific Function
cytochrome-b5 reductase activity, acting on NAD(P)H
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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in retinoid metabolism. Hydroxylates all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may modulate atRA signaling and clearance. Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase)
Specific Function
arachidonic acid epoxygenase activity
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. [Article]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
Specific Function
antioxidant activity
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
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. [Article]
  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. [Article]
  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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Major thyroid hormone transport protein in serum
Specific Function
serine-type endopeptidase inhibitor activity
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. [Article]
  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
Mediates the Na(+)-independent high affinity transport of organic anions such as the thyroid hormones L-thyroxine (T4), L-thyroxine sulfate (T4S), and 3,3',5'-triiodo-L-thyronine (reverse T3, rT3) at the plasma membrane (PubMed:12351693, PubMed:18566113, PubMed:19129463). Regulates T4 levels in different brain regions by transporting T4, and also by serving as an export pump for T4S, which is a source of T4 after hydrolysis by local sulfatases (PubMed:18566113). Increases the access of these substrates to the intracellular sites where they are metabolized by the deiodinases (PubMed:18566113). Other potential substrates, such as triiodothyronine (T3), 17-beta-glucuronosyl estradiol (17beta-estradiol 17-O-(beta-D-glucuronate)), estrone-3-sulfate (E1S) and sulfobromophthalein (BSP) are transported with much lower efficiency (PubMed:12351693, PubMed:19129463). Transports T4 and E1S in a pH-insensitive manner (PubMed:19129463). Facilitates the transport of thyroid hormones across the blood-brain barrier and into glia and neuronal cells in the brain (PubMed:30296914)
Specific Function
bile acid transmembrane transporter activity
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. [Article]
  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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
Specific Function
ABC-type xenobiotic transporter activity
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
ATP-dependent translocase ABCB1
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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
ATP-dependent transporter of the ATP-binding cassette (ABC) family that binds and hydrolyzes ATP to enable active transport of various substrates including many drugs, toxicants and endogenous compound across cell membranes. Transports a wide variety of conjugated organic anions such as sulfate-, glucuronide- and glutathione (GSH)-conjugates of endo- and xenobiotics substrates (PubMed:10220572, PubMed:10421658, PubMed:11500505, PubMed:16332456). Mediates hepatobiliary excretion of mono- and bis-glucuronidated bilirubin molecules and therefore play an important role in bilirubin detoxification (PubMed:10421658). Mediates also hepatobiliary excretion of others glucuronide conjugates such as 17beta-estradiol 17-glucosiduronic acid and leukotriene C4 (PubMed:11500505). Transports sulfated bile salt such as taurolithocholate sulfate (PubMed:16332456). Transports various anticancer drugs, such as anthracycline, vinca alkaloid and methotrexate and HIV-drugs such as protease inhibitors (PubMed:10220572, PubMed:11500505, PubMed:12441801). Confers resistance to several anti-cancer drugs including cisplatin, doxorubicin, epirubicin, methotrexate, etoposide and vincristine (PubMed:10220572, PubMed:11500505)
Specific Function
ABC-type glutathione S-conjugate transporter activity
Gene Name
ABCC2
Uniprot ID
Q92887
Uniprot Name
ATP-binding cassette sub-family C member 2
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. [Article]
  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. [Article]
  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. [Article]

Drug created at June 13, 2005 13:24 / Updated at October 21, 2024 08:50