PHENYTOIN

Details

Stereochemistry	ACHIRAL
Molecular Formula	C15H12N2O2
Molecular Weight	252.268
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

O=C1NC(=O)C(N1)(C2=CC=CC=C2)C3=CC=CC=C3

InChI

InChIKey=CXOFVDLJLONNDW-UHFFFAOYSA-N

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)

HIDE SMILES / InChI

Molecular Formula	C15H12N2O2
Molecular Weight	252.268
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

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

Description

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	Inhibitor 8,504	10.4 µM [EC50]
Sodium channel protein type III alpha subunit 18	Inhibitor 8,504	52.5 µM [EC50]
Sodium channel protein type VIII alpha subunit 7	Inhibitor 8,504	20.0 µM [EC50]
Sodium channel protein type I alpha subunit 15	Inhibitor 8,504	19.9 µM [EC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Seizures 9	Primary		Approved 8,583	DILANTIN-125
Status epilepticus 12	Primary		Approved 8,583	CEREBYX

C_max

Value	Dose	Co-administered	Analyte	Population
1.176 μg/mL	100 mg single, oral		PHENYTOIN plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
32.172 μg × h/mL	100 mg single, oral		PHENYTOIN plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
15.49 h	100 mg single, oral		PHENYTOIN plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
600 mg single, oral Highest studied dose	unhealthy, 31 years
20 g single, oral Overdose	unhealthy, 41 years	Other AEs: Sinus bradycardia, Hypotension...
5 g single, oral Overdose	unhealthy, 49 years	Other AEs: Acute respiratory failure...
60 mg/kg multiple, intravenous Overdose	unhealthy, 7 years	Other AEs: Encephalopathy...
2 g single, oral Overdose	unhealthy, adult	Other AEs: Nystagmus, Ataxia...

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AEs

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AE	Significance	Dose	Population
Sinus bradycardia	1 patient	20 g single, oral Overdose	unhealthy, 41 years
Hypotension	severe, 1 patient	20 g single, oral Overdose	unhealthy, 41 years
Acute respiratory failure	1 patient	5 g single, oral Overdose	unhealthy, 49 years
Encephalopathy	1 patient	60 mg/kg multiple, intravenous Overdose	unhealthy, 7 years
Ataxia	grade 5	2 g single, oral Overdose	unhealthy, adult

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,946	substrate 1,193 inhibitor 2,438 inducer 440		inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1,741 OATP1B1 1,079 OATP1B3 961 UGT1A6 136 UGT1A9 148 UGT2B15 84	CYP2C8 810 CYP2C19 1,119 P-gp 2,052	CYP2C19 329 CYP3A 142 UGT 32 CYP2B6 669 CYP2C8 198

Drug as perpetrator

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Target	Modality	Activity
OATP1B1 1,095	inhibitor 4,027	no
OATP1B3 970	inhibitor 4,027	no
P-gp 1,932	inhibitor 4,027	weak
UGT1A9 155	inhibitor 4,027	yes [IC50 145 uM]
UGT1A6 171	inhibitor 4,027	yes [IC50 280 uM]

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Drug as victim

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Target	Modality	Activity	Clinical evidence
P-gp 2,052	substrate 4,014	no
CYP2C19 1,119	substrate 4,014	yes
CYP2C8 810	substrate 4,014	yes
CYP3A4 1,946	substrate 4,014	yes	likely (co-administration study)
CYP2C9 1,193	substrate 4,014	yes	yes (co-administration study)

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2,263	inhibitor 2,237

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Sourcing

Sourcing

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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
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

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PubMed

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Title	Date	PubMed
Reversible renal failure and myositis caused by phenytoin hypersensitivity.	1976 Dec 13	1036571
Paradoxical seizures in phenytoin toxicity.	1999 Apr	10487084
Effects of anti-epileptic drugs on glutamine synthetase activity in mouse brain.	1999 Apr	10323596
A common mutation in the methylenetetrahydrofolate reductase gene is a determinant of hyperhomocysteinemia in epileptic patients receiving anticonvulsants.	1999 Aug	10459572
Expression and inducibility of the human bilirubin UDP-glucuronosyltransferase UGT1A1 in liver and cultured primary hepatocytes: evidence for both genetic and environmental influences.	1999 Aug	10421657

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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
Record UNII	6158TKW0C5
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

DILANTIN

Preferred Name

English

PHENYTOIN

Official Name

English

PHENYTOIN [MI]

Common Name

English

PHENYTOIN [USP-RS]

Common Name

English

EPAMIN

Brand Name

English

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Classification Tree

Code System

Code

WHO ESSENTIAL MEDICINES LIST

WHO-ESSENTIAL MEDICINES LIST

05

Hydantoin derivatives

WHO-VATC

QN03AB52

Decreased Disorganized Electrical Activity

NDF-RT

N0000008486

FDA ORPHAN DRUG

43490

WHO-VATC

QN03AB02

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Code System

Code

Type

Description

DAILYMED

6158TKW0C5

PRIMARY

NSC

8722

PRIMARY

NDF-RT

N0000190118

PRIMARY

Cytochrome P450 3A Inducers [MoA]

ECHA (EC/EINECS)

200-328-6

PRIMARY

NDF-RT

N0000191267

PRIMARY

Cytochrome P450 2D6 Inducers [MoA]

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Related Record

Type

Details


					TB51DM4UX4

SODIUM CHANNEL PROTEIN TYPE 3 SUBUNIT ALPHA

TARGET -> INHIBITOR

Qualification:

EC50

Amount:


					805SU96HKF

CYTOCHROME P450 3A5

METABOLIC ENZYME -> INDUCER


					4182431BJH

PHENYTOIN SODIUM

SALT/SOLVATE -> PARENT

Amount:


					6158TKW0C5

PHENYTOIN

BASIS OF STRENGTH->SUBSTANCE

Interaction Type:

ASSAY (TITRATION)

Qualification:

EP

Amount:


					081I12ZA58

CYTOCHROME P450 2C19

METABOLIC ENZYME -> INDUCER

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Type

Details


					G702A8B63R

4-HYDROXYPHENYTOIN O-GLUCURONIDE

METABOLITE -> PARENT

Comments:

UGT1A isoforms (UGT1A1, UGT1A4, UGT1A6, and UGT1A9) are involved in the glucuronosyltransferase activity of 4?-HPPH in humans

Interaction Type:

MAJOR

Qualification:

PLASMA

Amount:


					EH7VK7N06H

4-HYDROXYPHENYTOIN, (R)-

METABOLITE INACTIVE -> PARENT

Comments:

(1:1) R:S, by CYP2C19

Qualification:

Scientific Literature

Amount:


					NJ1YQ8177I

4-HYDROXYPHENYTOIN, (S)-

METABOLITE INACTIVE -> PARENT

Comments:

major metabolite, mainly by CYP2C9

Interaction Type:

MAJOR

Qualification:

Scientific Literature

Amount:


					EN5USZ96RX

5,5-BIS(4-HYDROXYPHENYL)HYDANTOIN

METABOLITE -> PARENT

Interaction Type:

MINOR

Amount:


					L42OQX7ZQY

4-HYDROXYPHENYTOIN

METABOLITE -> PARENT

Interaction Type:

MAJOR

Amount:

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Type

Details


					C15I92344M

DIPHENYLGLYCOLURIL, CIS-

IMPURITY -> PARENT

Comments:

For the calculation of contents, multiply the peak areas by 1.7

Interaction Type:

CHROMATOGRAPHIC PURITY (HPLC/UV)

Qualification:

EP

Amount:


					7VLR55452Z

FOSPHENYTOIN SODIUM

PARENT -> IMPURITY

Interaction Type:

CHROMATOGRAPHIC PURITY (HPLC/UV)

Qualification:

USP

Amount:


					701M4TTV9O

BENZOPHENONE

IMPURITY -> PARENT

Comments:

UNSPECIFIED

Qualification:

EP

Amount:


					8WSX411Z31

5-(P-METHYLPHENYL)-5-PHENYLHYDANTOIN

IMPURITY -> PARENT

Comments:

UNSPECIFIED

Qualification:

EP

Amount:


					701M4TTV9O

BENZOPHENONE

IMPURITY -> PARENT

Interaction Type:

CHROMATOGRAPHIC PURITY (HPLC/UV)

Qualification:

USP

Amount:

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Type

Details


					6158TKW0C5

PHENYTOIN

ACTIVE MOIETY

Amount:

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Name	Property Type	Parameters
Biological Half-life	PHARMACOKINETIC

Volume of Distribution	PHARMACOKINETIC	Population PHARMACOKINETIC Population PHARMACOKINETIC Population PHARMACOKINETIC Population PHARMACOKINETIC Population PHARMACOKINETIC

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

Drug as perpetrator