Details
| Stereochemistry | ACHIRAL |
| Molecular Formula | C16H13N2O6P.2Na.7H2O |
| Molecular Weight | 532.3445 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
O.O.O.O.O.O.O.[Na+].[Na+].[O-]P([O-])(=O)OCN1C(=O)NC(C1=O)(C2=CC=CC=C2)C3=CC=CC=C3
InChI
InChIKey=KFGQDIBFHJVFDV-UHFFFAOYSA-L
InChI=1S/C16H15N2O6P.2Na.7H2O/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);;;7*1H2/q;2*+1;;;;;;;/p-2
DescriptionCurator's Comment: Description was created based on several sources, including
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020450s020lbl.pdf
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 | Condition | Potency |
|---|---|---|---|
Target ID: CHEMBL4187 |
10.4 µM [EC50] | ||
Target ID: CHEMBL5163 |
52.5 µM [EC50] | ||
Target ID: CHEMBL5202 |
20.0 µM [EC50] | ||
Target ID: CHEMBL1845 |
19.9 µM [EC50] |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Primary | DILANTIN-125 Approved UseDilantin (phenytoin) is indicated for the control of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures Launch Date1953 |
|||
| Primary | CEREBYX Approved UseCEREBYX 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 Date1996 |
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
1.176 μg/mL |
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 |
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 |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
15.49 h |
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: |
unhealthy, 31 years n = 15 Health Status: unhealthy Condition: epilepsy Age Group: 31 years Sex: M+F Population Size: 15 Sources: |
|
20 g single, oral Overdose Dose: 20 g Route: oral Route: single Dose: 20 g Co-administed with:: glibenclamide(500 mg) Sources: |
unhealthy, 41 years n = 1 Health Status: unhealthy Age Group: 41 years Sex: F Population Size: 1 Sources: |
Other AEs: Sinus bradycardia, Hypotension... Other AEs: Sinus bradycardia (1 patient) Sources: Hypotension (severe, 1 patient) |
5 g single, oral Overdose |
unhealthy, 49 years n = 1 Health Status: unhealthy Age Group: 49 years Sex: M Population Size: 1 Sources: |
Other AEs: Acute respiratory failure... |
60 mg/kg multiple, intravenous (total) Overdose Dose: 60 mg/kg Route: intravenous Route: multiple Dose: 60 mg/kg Sources: |
unhealthy, 7 years n = 1 Health Status: unhealthy Age Group: 7 years Sex: M Population Size: 1 Sources: |
Other AEs: Encephalopathy... |
2 g single, oral Overdose Dose: 2 g Route: oral Route: single Dose: 2 g Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sources: |
Other AEs: Nystagmus, Ataxia... Other AEs: Nystagmus (grade 5) Sources: 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) |
10 mg/kg single, intramuscular (starting) Dose: 10 mg/kg Route: intramuscular Route: single Dose: 10 mg/kg Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sources: |
Other AEs: Hypotension, Cardiac arrhythmias... Other AEs: Hypotension (severe) Sources: Cardiac arrhythmias |
10 mg/kg single, intravenous (starting) Dose: 10 mg/kg Route: intravenous Route: single Dose: 10 mg/kg Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sources: |
Other AEs: Hypotension, Cardiac arrhythmias... Other AEs: Hypotension (severe) Sources: Cardiac arrhythmias |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| Sinus bradycardia | 1 patient | 20 g single, oral Overdose Dose: 20 g Route: oral Route: single Dose: 20 g Co-administed with:: glibenclamide(500 mg) Sources: |
unhealthy, 41 years n = 1 Health Status: unhealthy Age Group: 41 years Sex: F Population Size: 1 Sources: |
| Hypotension | severe, 1 patient | 20 g single, oral Overdose Dose: 20 g Route: oral Route: single Dose: 20 g Co-administed with:: glibenclamide(500 mg) Sources: |
unhealthy, 41 years n = 1 Health Status: unhealthy Age Group: 41 years Sex: F Population Size: 1 Sources: |
| Acute respiratory failure | 1 patient | 5 g single, oral Overdose |
unhealthy, 49 years n = 1 Health Status: unhealthy Age Group: 49 years Sex: M Population Size: 1 Sources: |
| Encephalopathy | 1 patient | 60 mg/kg multiple, intravenous (total) Overdose Dose: 60 mg/kg Route: intravenous Route: multiple Dose: 60 mg/kg Sources: |
unhealthy, 7 years n = 1 Health Status: unhealthy Age Group: 7 years Sex: M Population Size: 1 Sources: |
| Ataxia | grade 5 | 2 g single, oral Overdose Dose: 2 g Route: oral Route: single Dose: 2 g Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sources: |
| Blurred vision | grade 5 | 2 g single, oral Overdose Dose: 2 g Route: oral Route: single Dose: 2 g Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sources: |
| Dysarthria | grade 5 | 2 g single, oral Overdose Dose: 2 g Route: oral Route: single Dose: 2 g Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sources: |
| Hyperreflexia | grade 5 | 2 g single, oral Overdose Dose: 2 g Route: oral Route: single Dose: 2 g Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sources: |
| Lethargy | grade 5 | 2 g single, oral Overdose Dose: 2 g Route: oral Route: single Dose: 2 g Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sources: |
| Nausea | grade 5 | 2 g single, oral Overdose Dose: 2 g Route: oral Route: single Dose: 2 g Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sources: |
| Nystagmus | grade 5 | 2 g single, oral Overdose Dose: 2 g Route: oral Route: single Dose: 2 g Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sources: |
| Slurred speech | grade 5 | 2 g single, oral Overdose Dose: 2 g Route: oral Route: single Dose: 2 g Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sources: |
| Tremor | grade 5 | 2 g single, oral Overdose Dose: 2 g Route: oral Route: single Dose: 2 g Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sources: |
| Vomiting | grade 5 | 2 g single, oral Overdose Dose: 2 g Route: oral Route: single Dose: 2 g Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sources: |
| Cardiac arrhythmias | 10 mg/kg single, intramuscular (starting) Dose: 10 mg/kg Route: intramuscular Route: single Dose: 10 mg/kg Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sources: |
|
| Hypotension | severe | 10 mg/kg single, intramuscular (starting) Dose: 10 mg/kg Route: intramuscular Route: single Dose: 10 mg/kg Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sources: |
| Cardiac arrhythmias | 10 mg/kg single, intravenous (starting) Dose: 10 mg/kg Route: intravenous Route: single Dose: 10 mg/kg Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sources: |
|
| Hypotension | severe | 10 mg/kg single, intravenous (starting) Dose: 10 mg/kg Route: intravenous Route: single Dose: 10 mg/kg Sources: |
unhealthy, adult Health Status: unhealthy Age Group: adult Sources: |
Overview
| CYP3A4 | CYP2C9 | CYP2D6 | hERG |
|---|---|---|---|
OverviewOther
| Other Inhibitor | Other Substrate | Other Inducer |
|---|---|---|
Drug as perpetrator
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
| no | ||||
| no | ||||
Page: 6.0 |
weak | |||
Page: 7.0 |
yes [IC50 145 uM] | |||
Page: 7.0 |
yes [IC50 280 uM] | |||
Page: 7.0 |
yes [IC50 607 uM] | |||
| yes | ||||
| yes | likely (co-administration study) Comment: See https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/084427s042lbl.pdf#page=10 |
|||
| yes | likely (co-administration study) Comment: See https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/084427s042lbl.pdf#page=10 |
|||
Page: 46.0 |
yes | likely (co-administration study) Comment: See https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/084427s042lbl.pdf#page=11 Page: 46.0 |
||
| yes | likely (co-administration study) Comment: See https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/084427s042lbl.pdf#page=9 |
|||
| yes | likely (co-administration study) Comment: See https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/084427s042lbl.pdf#page=11 |
|||
| 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 |
Drug as victim
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
Page: 6.0 |
no | |||
| yes | ||||
Page: 7.0 |
yes | |||
| yes | likely (co-administration study) Comment: See https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/084427s042lbl.pdf#page=9 |
|||
| 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 Page: 8.0 |
Tox targets
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
PubMed
| Title | Date | PubMed |
|---|---|---|
| Harmful effect of megadoses of vitamins: electroencephalogram abnormalities and seizures induced by intravenous folate in drug-treated epileptics. | 1975 Jan |
|
| The influence of aldosterone and anticonvulsant drugs on electroencephalographic and clinical disturbances induced by the spirolactone derivative, potassium canrenoate. | 1975 Jan |
|
| Reversible renal failure and myositis caused by phenytoin hypersensitivity. | 1976 Dec 13 |
|
| Assessment of colour vision in epileptic patients exposed to single-drug therapy. | 1999 |
|
| Paradoxical seizures in phenytoin toxicity. | 1999 Apr |
|
| Effects of anti-epileptic drugs on glutamine synthetase activity in mouse brain. | 1999 Apr |
|
| Extremely acute phenytoin-induced peripheral neuropathy. | 1999 Apr |
|
| A common mutation in the methylenetetrahydrofolate reductase gene is a determinant of hyperhomocysteinemia in epileptic patients receiving anticonvulsants. | 1999 Aug |
|
| Atrioventricular septal defect with separate right and left atrioventricular valvar orifices in a patient with foetal hydantoin syndrome. | 1999 Jan |
|
| Distinct features of seizures induced by cocaine and amphetamine analogs. | 1999 Jul 21 |
|
| Dyskinesia induced by phenytoin. | 1999 Jun |
|
| [Atrioventricular junctional arrhythmia due to oral phenytoin intoxication]. | 1999 Mar 15 |
|
| Retro-peritoneal cystic lymphangioma in association with fetal hydantoin syndrome. | 1999 Mar-Apr |
|
| Side effects and mortality associated with use of phenytoin for early posttraumatic seizure prophylaxis. | 1999 Oct |
|
| Incidence and clinical consequence of the purple glove syndrome in patients receiving intravenous phenytoin. | 1999 Oct 22 |
|
| Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin. | 1999 Sep |
|
| Anticonvulsant-induced suppression of IFN-gamma production by lymphocytes obtained from cervical lymph nodes in glioma-bearing mice. | 2000 Apr |
|
| Protection from phenytoin-induced cognitive deficit by Bacopa monniera, a reputed Indian nootropic plant. | 2000 Aug |
|
| Acute fulminant hepatic failure in a woman treated with phenytoin and trimethoprim-sulfamethoxazole. | 2000 Dec |
|
| Phenytoin, midazolam, and naloxone protect against fentanyl-induced brain damage in rats. | 2000 Dec |
|
| Effects of anticonvulsants on local anaesthetic-induced neurotoxicity in rats. | 2000 Feb |
|
| Immunolocalizaiton of c-Myc and bcl-2 proto-oncogene products in gingival hyperplasia induced by nifedipine and phenytoin. | 2000 Jan |
|
| Refractory idiopathic absence status epilepticus: A probable paradoxical effect of phenytoin and carbamazepine. | 2000 Jul |
|
| Phenytoin and cyclosporin A suppress the expression of MMP-1, TIMP-1, and cathepsin L, but not cathepsin B in cultured gingival fibroblasts. | 2000 Jun |
|
| Incidence of intravenous site reactions in neurotrauma patients receiving valproate or phenytoin. | 2000 Jun |
|
| Seizure-inducing paradoxical reaction to antiepileptic drugs. | 2000 Jun |
|
| Purple glove syndrome caused by oral administration of phenytoin. | 2000 Nov |
|
| Activation of cytochrome P450 gene expression in the rat brain by phenobarbital-like inducers. | 2000 Sep |
|
| Evaluation of the neuroprotective effects of sodium channel blockers after spinal cord injury: improved behavioral and neuroanatomical recovery with riluzole. | 2001 Apr |
|
| Decreases in phenytoin hydroxylation activities catalyzed by liver microsomal cytochrome P450 enzymes in phenytoin-treated rats. | 2001 Apr |
|
| Inhibition of phenytoin hydroxylation in human liver microsomes by several selective serotonin re-uptake inhibitors. | 2001 Apr |
|
| The teratogenicity of anticonvulsant drugs. | 2001 Apr 12 |
|
| Nitroso-urea-cisplatin-based chemotherapy associated with valproate: increase of haematologic toxicity. | 2001 Feb |
|
| Antiepileptic drug withdrawal in patients with temporal lobe epilepsy undergoing presurgical video-EEG monitoring. | 2001 Feb |
|
| Glutamate receptor antagonists differentially affect the protective activity of conventional antiepileptics against amygdala-kindled seizures in rats. | 2001 Feb |
|
| Phenytoin intoxication induced by fluvoxamine. | 2001 Feb |
|
| Rufinamide: a double-blind, placebo-controlled proof of principle trial in patients with epilepsy. | 2001 Feb |
|
| Possible function of astrocyte cytochrome P450 in control of xenobiotic phenytoin in the brain: in vitro studies on murine astrocyte primary cultures. | 2001 Feb |
|
| [Maintenance dose requirement for phenytoin is lowered in genetically impaired drug metabolism independent of concommitant use of other antiepileptics]. | 2001 Feb 17 |
|
| [Febrile convulsions, Treatment and prognosis]. | 2001 Feb 19 |
|
| Interferon-alpha2a and 13-cis-retinoic acid with radiation treatment for high-grade glioma. | 2001 Jan |
|
| Electrophysiological and pharmacological properties of the human brain type IIA Na+ channel expressed in a stable mammalian cell line. | 2001 Jan |
|
| Ritonavir-induced carbamazepine toxicity. | 2001 Jan |
|
| Treatment of nonfebrile status epilepticus in Rochester, Minn, from 1965 through 1984. | 2001 Jan |
|
| Effects of phenytoin on glutathione status and oxidative stress biomarker gene mRNA levels in cultured precision human liver slices. | 2001 Jan |
|
| Successful treatment of antiepileptic drug hypersensitivity syndrome with intravenous immune globulin. | 2001 Jan |
|
| Myotoxicity studies of injectable biodegradable in-situ forming drug delivery systems. | 2001 Jan 5 |
|
| 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 |
|
| Volume-selective proton MR spectroscopy for in-vitro quantification of anticonvulsants. | 2001 Mar |
|
| Efficacy of levetiracetam versus fosphenytoin for the recurrence of seizures after status epilepticus. | 2017 Jun |
Sample Use Guides
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
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.
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SUB130399
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9X1NTA9SRP
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46174075
Created by
admin on Sat Dec 16 05:34:51 GMT 2023 , Edited by admin on Sat Dec 16 05:34:51 GMT 2023
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100000156465
Created by
admin on Sat Dec 16 05:34:51 GMT 2023 , Edited by admin on Sat Dec 16 05:34:51 GMT 2023
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PRIMARY |
ACTIVE MOIETY
PARENT (SALT/SOLVATE)
SUBSTANCE RECORD
