FOSPHENYTOIN

First approved in 1938

Details

Stereochemistry	ACHIRAL
Molecular Formula	C16H15N2O6P
Molecular Weight	362.2739
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OP(O)(=O)OCN1C(=O)NC(C1=O)(C2=CC=CC=C2)C3=CC=CC=C3

InChI

InChIKey=XWLUWCNOOVRFPX-UHFFFAOYSA-N

InChI=1S/C16H15N2O6P/c19-14-16(12-7-3-1-4-8-12,13-9-5-2-6-10-13)17-15(20)18(14)11-24-25(21,22)23/h1-10H,11H2,(H,17,20)(H2,21,22,23)

HIDE SMILES / InChI

Molecular Formula	C16H15N2O6P
Molecular Weight	362.2739
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/8981053
Curator's Comment: Description was created based on several sources, including http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020450s020lbl.pdf

Phenytoin is an anti-epileptic drug. Phenytoin has been used with much clinical success against all types of epileptiform seizures, except petit mal epilepsy. Phenytoin is a available for oral administration (tablets, capsules, suspension). CEREBYX® (fosphenytoin sodium injection) is a prodrug intended for parenteral administration; its active metabolite is phenytoin. CEREBYX should be used only when oral phenytoin administration is not possible. Although several potential targets for phenytoin action have been identified within the CNS (Na-K-ATPase, the GABAA receptor complex, ionotropic glutamate receptors, calcium channels and sigma binding sites) to date, though, the best evidence hinges on the inhibition of voltage-sensitive Na+ channels in the plasma membrane of neurons undergoing seizure activity.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Sodium channel protein type II alpha subunit 27 Target ID: CHEMBL4187 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8981053	Inhibitor 8228	10.4 µM [EC50]
Sodium channel protein type III alpha subunit 18 Target ID: CHEMBL5163 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8981053	Inhibitor 8228	52.5 µM [EC50]
Sodium channel protein type VIII alpha subunit 7 Target ID: CHEMBL5202 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8981053	Inhibitor 8228	20.0 µM [EC50]
Sodium channel protein type I alpha subunit 15 Target ID: CHEMBL1845 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8981053	Inhibitor 8228	19.9 µM [EC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Seizures 9 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/008762s055,010151s042lbl.pdf	Primary		Approved 8360	DILANTIN-125 Approved Use Dilantin (phenytoin) is indicated for the control of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures Launch Date -5.36025596E11
Status epilepticus 12 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020450s020lbl.pdf	Primary		Approved 8360	CEREBYX Approved Use CEREBYX is indicated for the control of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery. CEREBYX can also be substituted, short-term, for oral phenytoin. CEREBYX should be used only when oral phenytoin administration is not possible. CEREBYX must not be given orally. Launch Date 8.3911678E11

C_max

Value	Dose	Co-administered	Analyte	Population
1.176 μg/mL OTHER GOV https://www.accessdata.fda.gov/drugsatfda_docs/anda/98/40-298_Phenytoin%20Sodium_Bioeqr.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		PHENYTOIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
32.172 μg × h/mL OTHER GOV https://www.accessdata.fda.gov/drugsatfda_docs/anda/98/40-298_Phenytoin%20Sodium_Bioeqr.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		PHENYTOIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
15.49 h OTHER GOV https://www.accessdata.fda.gov/drugsatfda_docs/anda/98/40-298_Phenytoin%20Sodium_Bioeqr.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		PHENYTOIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

Doses

Dose	Population	Adverse events
600 mg single, oral Highest studied dose Dose: 600 mg Route: oral Route: single Dose: 600 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/040759lbl.pdf https://pubmed.ncbi.nlm.nih.gov/22454904	unhealthy, 31 years n = 15 Health Status: unhealthy Condition: epilepsy Age Group: 31 years Sex: M+F Population Size: 15 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/040759lbl.pdf https://pubmed.ncbi.nlm.nih.gov/22454904	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/040759lbl.pdf https://pubmed.ncbi.nlm.nih.gov/22454904
20 g single, oral Overdose Dose: 20 g Route: oral Route: single Dose: 20 g Co-administed with:: glibenclamide(500 mg) Sources: https://pubmed.ncbi.nlm.nih.gov/26312007/	unhealthy, 41 years n = 1 Health Status: unhealthy Age Group: 41 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/26312007/	Other AEs: Sinus bradycardia, Hypotension... Other AEs: Sinus bradycardia (1 patient) Hypotension (severe, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/26312007/
5 g single, oral Overdose Dose: 5 g Route: oral Route: single Dose: 5 g Sources: https://pubmed.ncbi.nlm.nih.gov/24307853/	unhealthy, 49 years n = 1 Health Status: unhealthy Age Group: 49 years Sex: M Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/24307853/	Other AEs: Acute respiratory failure... Other AEs: Acute respiratory failure (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/24307853/
60 mg/kg multiple, intravenous (total) Overdose Dose: 60 mg/kg Route: intravenous Route: multiple Dose: 60 mg/kg Sources: https://pubmed.ncbi.nlm.nih.gov/27756964/	unhealthy, 7 years n = 1 Health Status: unhealthy Age Group: 7 years Sex: M Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/27756964/	Other AEs: Encephalopathy... Other AEs: Encephalopathy (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/27756964/
2 g single, oral Overdose Dose: 2 g Route: oral Route: single Dose: 2 g Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/008762s065lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/008762s065lbl.pdf	Other AEs: Nystagmus, Ataxia... Other AEs: Nystagmus (grade 5) Ataxia (grade 5) Dysarthria (grade 5) Tremor (grade 5) Hyperreflexia (grade 5) Lethargy (grade 5) Slurred speech (grade 5) Blurred vision (grade 5) Nausea (grade 5) Vomiting (grade 5) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/008762s065lbl.pdf
10 mg/kg single, intramuscular (starting) Dose: 10 mg/kg Route: intramuscular Route: single Dose: 10 mg/kg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/010151s047s048lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/010151s047s048lbl.pdf	Other AEs: Hypotension, Cardiac arrhythmias... Other AEs: Hypotension (severe) Cardiac arrhythmias Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/010151s047s048lbl.pdf
10 mg/kg single, intravenous (starting) Dose: 10 mg/kg Route: intravenous Route: single Dose: 10 mg/kg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/010151s047s048lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/010151s047s048lbl.pdf	Other AEs: Hypotension, Cardiac arrhythmias... Other AEs: Hypotension (severe) Cardiac arrhythmias Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/010151s047s048lbl.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1709	substrate 1010 inhibitor 1752 inducer 383		inhibitor 1599

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1437 OATP1B1 781 OATP1B3 700 UGT1A6 108 UGT1A9 116 UGT2B15 64	CYP2C8 688 CYP2C19 985 P-gp 1527	CYP2C19 290 CYP3A 126 UGT 29 CYP2B6 538 CYP2C8 168

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
OATP1B1 796	inhibitor 3240 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376123/	no
OATP1B3 709	inhibitor 3240 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376123/	no
P-gp 1626	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/15961125/ Page: 6.0	weak
UGT1A9 121	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/15933229/ Page: 7.0	yes [IC50 145 uM]
UGT1A6 141	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/15933229/ Page: 7.0	yes [IC50 280 uM]
UGT2B15 64	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/15933229/ Page: 7.0	yes [IC50 607 uM]
UGT 58	inducer 1542 Sources: https://pubmed.ncbi.nlm.nih.gov/9606477	yes
CYP2B6 985	inducer 1542 Sources: https://pubmed.ncbi.nlm.nih.gov/9332469/	yes	likely (co-administration study) Comment: See https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/084427s042lbl.pdf#page=10 Sources: https://pubmed.ncbi.nlm.nih.gov/9332469/
CYP2C19 1537	inducer 1542 Sources: https://pubmed.ncbi.nlm.nih.gov/15247556/	yes	likely (co-administration study) Comment: See https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/084427s042lbl.pdf#page=10 Sources: https://pubmed.ncbi.nlm.nih.gov/15247556/
CYP2C8 955	inducer 1542 Sources: https://pubmed.ncbi.nlm.nih.gov/26721703/ Page: 46.0	yes	likely (co-administration study) Comment: See https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/084427s042lbl.pdf#page=11 Sources: https://pubmed.ncbi.nlm.nih.gov/26721703/ Page: 46.0
CYP2C9 1803	inducer 1542 Sources: https://pubmed.ncbi.nlm.nih.gov/15247556/	yes	likely (co-administration study) Comment: See https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/084427s042lbl.pdf#page=9 Sources: https://pubmed.ncbi.nlm.nih.gov/15247556/
CYP3A 295	inducer 1542 Sources: https://pubmed.ncbi.nlm.nih.gov/9606477	yes	likely (co-administration study) Comment: See https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/084427s042lbl.pdf#page=11 Sources: https://pubmed.ncbi.nlm.nih.gov/9606477
CYP2C9 1803	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/12235444/	yes	yes (co-administration study) Comment: mean AUC(0-24) of losartan was insignificantly increased by 17% when losartan was coadministered with phenytoin. See more on https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/084427s042lbl.pdf#page=9 Sources: https://pubmed.ncbi.nlm.nih.gov/12235444/

Drug as victim

Target	Modality	Activity	Clinical evidence
P-gp 1527	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/15961125/ Page: 6.0	no
CYP2C19 985	substrate 3326 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/084427s042lbl.pdf#page=8 Page: 8.0	yes
CYP2C8 688	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/8819299/ Page: 7.0	yes
CYP3A4 1709	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/11038165/	yes	likely (co-administration study) Comment: See https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/084427s042lbl.pdf#page=9 Sources: https://pubmed.ncbi.nlm.nih.gov/11038165/
CYP2C9 1010	substrate 3326 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/084427s042lbl.pdf#page=8; https://pubmed.ncbi.nlm.nih.gov/12235444/; Page: 8.0	yes	yes (co-administration study) Comment: Coadministration of losartan had no effect on the pharmacokinetics of phenytoin. See more on https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/084427s042lbl.pdf#page8 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/084427s042lbl.pdf#page=8; https://pubmed.ncbi.nlm.nih.gov/12235444/; Page: 8.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1632	inhibitor 1613 Sources: https://pubmed.ncbi.nlm.nih.gov/12948624/

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:8107	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:8107
ChemicalBook	CB3139264	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB3139264
MolPort	MolPort-001-785-683	https://www.molport.com/shop/molecule-link/MolPort-001-785-683
MolPort	MolPort-002-365-712	https://www.molport.com/shop/molecule-link/MolPort-002-365-712
MolPort	MolPort-023-220-142	https://www.molport.com/shop/molecule-link/MolPort-023-220-142
Selleck Chemicals	Phenytoin-Lepitoin	http://www.selleckchem.com/products/Phenytoin-Lepitoin.html
ZINC	ZINC000002510358	http://zinc15.docking.org/substances/ZINC000002510358
eMolecules	13434342	https://www.emolecules.com/cgi-bin/more?vid=13434342
eMolecules	507449	https://www.emolecules.com/cgi-bin/more?vid=507449
eMolecules	5420227	https://www.emolecules.com/cgi-bin/more?vid=5420227

PubMed

Title	Date	PubMed
The influence of aldosterone and anticonvulsant drugs on electroencephalographic and clinical disturbances induced by the spirolactone derivative, potassium canrenoate.	1975 Jan	1110371
Anticonvulsant-induced dyskinesias: a comparison with dyskinesias induced by neuroleptics.	1976 Dec	1011032
Assessment of colour vision in epileptic patients exposed to single-drug therapy.	1999	10343150
Paradoxical seizures in phenytoin toxicity.	1999 Apr	10487084
Effects of anti-epileptic drugs on glutamine synthetase activity in mouse brain.	1999 Apr	10323596
Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele.	1999 Feb	10208645
Carbamazepine-associated severe bile duct injury.	1999 Feb	10022661
Atrioventricular septal defect with separate right and left atrioventricular valvar orifices in a patient with foetal hydantoin syndrome.	1999 Jan	10323545
Cognitive dysfunction induced by phenytoin and valproate in rats: effect of nitric oxide.	1999 Jul	10776488
A reporter gene assay to assess the molecular mechanisms of xenobiotic-dependent induction of the human CYP3A4 gene in vitro.	1999 Mar	10219967
[Atrioventricular junctional arrhythmia due to oral phenytoin intoxication].	1999 Mar 15	10914260
Systemic vasculitis associated with long-term phenytoin therapy.	1999 Mar 26	10210297
Retro-peritoneal cystic lymphangioma in association with fetal hydantoin syndrome.	1999 Mar-Apr	10798073
Developmental effects of phenytoin may differ depending on sex of offspring.	1999 Mar-Apr	10192272
Side effects and mortality associated with use of phenytoin for early posttraumatic seizure prophylaxis.	1999 Oct	10507379
[Acute liver failure by diphenylhydantoin].	2000	10925722
Anticonvulsant-induced suppression of IFN-gamma production by lymphocytes obtained from cervical lymph nodes in glioma-bearing mice.	2000 Apr	10982153
[Phenytoin-induced hypersensitivity reaction with liver failure].	2000 Apr 13	10823022
Protection from phenytoin-induced cognitive deficit by Bacopa monniera, a reputed Indian nootropic plant.	2000 Aug	10940574
Phenytoin, midazolam, and naloxone protect against fentanyl-induced brain damage in rats.	2000 Dec	11093997
Effects of anticonvulsants on local anaesthetic-induced neurotoxicity in rats.	2000 Feb	10728915
An embryoprotective role for glucose-6-phosphate dehydrogenase in developmental oxidative stress and chemical teratogenesis.	2000 Jan	10627286
Incidence of intravenous site reactions in neurotrauma patients receiving valproate or phenytoin.	2000 Jun	10860128
Catalytic activity of three variants (Ile, Leu, and Thr) at amino acid residue 359 in human CYP2C9 gene and simultaneous detection using single-strand conformation polymorphism analysis.	2000 Jun	10850388
Seizure-inducing paradoxical reaction to antiepileptic drugs.	2000 Jun	10838112
Purple glove syndrome caused by oral administration of phenytoin.	2000 Nov	11108512
I. The modulatory effect in genotoxic responses due to age and duration of PHT-therapy in epileptic patients.	2001	11223891
Decreases in phenytoin hydroxylation activities catalyzed by liver microsomal cytochrome P450 enzymes in phenytoin-treated rats.	2001 Apr	11259327
Inhibition of phenytoin hydroxylation in human liver microsomes by several selective serotonin re-uptake inhibitors.	2001 Apr	11255075
Nitroso-urea-cisplatin-based chemotherapy associated with valproate: increase of haematologic toxicity.	2001 Feb	11300327
Glutamate receptor antagonists differentially affect the protective activity of conventional antiepileptics against amygdala-kindled seizures in rats.	2001 Feb	11226813
Possible function of astrocyte cytochrome P450 in control of xenobiotic phenytoin in the brain: in vitro studies on murine astrocyte primary cultures.	2001 Feb	11161626
Interferon-alpha2a and 13-cis-retinoic acid with radiation treatment for high-grade glioma.	2001 Jan	11305415
Inhibition of human cytochrome P450 isoforms by nonnucleoside reverse transcriptase inhibitors.	2001 Jan	11225565
Electrophysiological and pharmacological properties of the human brain type IIA Na+ channel expressed in a stable mammalian cell line.	2001 Jan	11212204
Ritonavir-induced carbamazepine toxicity.	2001 Jan	11197575
Treatment of nonfebrile status epilepticus in Rochester, Minn, from 1965 through 1984.	2001 Jan	11155411
Effects of phenytoin on glutathione status and oxidative stress biomarker gene mRNA levels in cultured precision human liver slices.	2001 Jan	11134551
Successful treatment of antiepileptic drug hypersensitivity syndrome with intravenous immune globulin.	2001 Jan	11134478
N6-cyclohexyladenosine and 3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid enhance the effect of antiepileptic drugs against induced seizures in mice.	2001 Jan-Apr	11302789
Volume-selective proton MR spectroscopy for in-vitro quantification of anticonvulsants.	2001 Mar	11305752

Patents

Sample Use Guides

In Vivo Use Guide

Dilantin-125® (Phenytoin Oral Suspension, USP), each 5 ml of suspension contains 125 mg of phenytoin: Patients who have received no previous treatment may be started on one teaspoonful (5 mL) of Dilantin-125 Suspension three times daily, and the dose is then adjusted to suit individual requirements. An increase to five teaspoonfuls daily may be made, if necessary. CEREBYX® (fosphenytoin sodium injection) is a prodrug intended for parenteral administration; its active metabolite is phenytoin. 1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg phenytoin sodium equivalents (PE). CEREBYX should be used only when oral phenytoin administration is not possible. Dosage (Status Epilepticus): The loading dose of CEREBYX is 15 to 20 mg PE/kg administered at 100 to 150 mg PE/min.

Route of Administration: Other

In Vitro Use Guide

Exposure of human adult keratinocytes (HaCaT cells) for 48 h to alkyd nanoemulsions producing phenytoin concentrations of 3.125-200 μg/mL resulted in relative cell viability readings using tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide of 100% confirming nontoxicity and suggesting cell proliferation activity.

Substance Class	Chemical Created by `admin` on `Wed Jul 05 23:14:59 UTC 2023` Edited by `admin` on `Wed Jul 05 23:14:59 UTC 2023`
Record UNII	B4SF212641
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

FOSPHENYTOIN

Official Name

English

FOSPHENYTOIN [HSDB]

Common Name

English

FOSPHENYTOIN [VANDF]

Common Name

English

3-(HYDROXYMETHYL)-5,5-DIPHENYLHYDANTOIN, PHOSPHATE (ESTER)

Common Name

English

Fosphenytoin [WHO-DD]

Common Name

English

FOSPHENYTOIN [MI]

Common Name

English

fosphenytoin [INN]

Common Name

English

NP-06

Common Name

English

2,4-IMIDAZOLIDINEDIONE, 5,5-DIPHENYL-3-((PHOSPHONOOXY)METHYL)-

Systematic Name

English

Classification Tree Code System Code

NDF-RT

N0000008486