Top Gene Interactions
- Metabolism: Primarily hepatic. The majority of the dose (up to 90%) is metabolized to 5-(4'-hydroxyphenyl)-5-phenylhydantoin (p-HPPH). This metabolite undergoes further glucuronidation and is excreted into the urine. CYP2C19 and CYP2C9 catalyze the aforementioned reaction. Route of Elimination: Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion. Half Life: 22 hours (range of 7 to 42 hours)
- Uses/Sources: For the control of generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery.
- Health Effects: May cause a potentially dangerous rash that may develop into Stevens Johnson syndrome, an extremely rare but potentially fatal skin disease.
- Symptoms: Symptoms of overdose include coma, difficulty in pronouncing words correctly, involuntary eye movement, lack of muscle coordination, low blood pressure, nausea, sluggishness, slurred speech, tremors, and vomiting.
- Treatment: Treatment is nonspecific since there is no known antidote. The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients. (L1712)
- Route of Exposure: Intravenous, Oral, Intramuscular. Bioavailability 70-100% oral, 24.4% for rectal and intravenous administration. Rapid rate of absorption with peak blood concentration expected in 1½ to 3 hours.
- Carcinogenicity: 2B, possibly carcinogenic to humans. (L135)
- Toxicity: Oral, mouse: LD<sub>50</sub> = 150 mg/kg; Oral, rat: LD<sub>50</sub> = 1635 mg/kg.
Mechanism of Action
|Target Name||Mechanism of Action||References|
Potassium voltage-gated channel subfamily H member 2
Sodium channel protein type 2 subunit alpha
Sodium channel protein type 3 subunit alpha
Sodium channel protein type 4 subunit alpha
Nuclear receptor subfamily 1 group I member 2
Sodium-dependent dopamine transporter
Cytochrome P450 2C9
Bile acid receptor
Sodium channel protein type 1 subunit alpha
Sodium channel protein type 5 subunit alpha
|Phenytoin acts on sodium channels on the neuronal cell membrane, limiting the spread of seizure activity and reducing seizure propagation. By promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of post-tetanic potentiation at synapses. Loss of post-tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas.||