Voltage-gated Na+ channels (VGSCs)
Voltage-gated sodium channels (inactivated state) [5]

One anti-oxidant medication is phenytoin. It is ineffective for original comprehensive advantages like the Absence Plan or muscle matrix tonics, but it is helpful for direct matrix tonics with powerful partial and comprehensive effects. It is believed that phenytoin achieves this by voltage gating. Channels can be blocked by voltage to stop programming [2]. Low neuronal affinity for resting channels at supra-thigh membrane potential is exhibited by phenytoin [3]. More binding and blocking happen when the channel and the upper portion of the metaphase change to an open, inactive state. Because the blocking effect is very usage dependent, it builds up after extended or frequent activation, like when a reference occurs. Since phenytoin's blocking of sodium channels acts slowly, it does not quickly alter the current time course or burst the strongest event potentials that are broken down by synapses of ordinary duration. Therefore, without significantly affecting ictal activity, phenytoin can occasionally decrease pathological hyperexcitability in phase patients. Additionally, phenytoin causes electrical current to burst continuously, which may be crucial for managing engineering data. One class 1b antiarrhythmic medication is phenytoin [4].

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Treatment of human breast cancer cell lines (MDA-MB-231, MCF-7) with Phenytoin (5,5-Diphenylhydantoin) resulted in concentration-dependent inhibition of cell proliferation. At concentrations of 50 μM, 100 μM, and 200 μM, the drug significantly reduced colony formation efficiency and induced G1 phase cell cycle arrest. It also suppressed cell migration and invasion by downregulating the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 at both mRNA and protein levels. Additionally, Phenytoin (5,5-Diphenylhydantoin) promoted apoptosis of breast cancer cells, as evidenced by increased Annexin V-positive cells and upregulated expression of cleaved caspase-3[1]
- In rat hippocampal neurons, Phenytoin (5,5-Diphenylhydantoin) bound slowly to inactivated sodium channels, prolonging the inactivation state and reducing the number of functional sodium channels available for activation. This binding was voltage-dependent, with higher affinity for channels in the inactivated conformation compared to the resting state. The drug significantly inhibited sodium current amplitude in a concentration-dependent manner without altering the voltage dependence of channel activation[5]
- At the neuromuscular junction of isolated rat phrenic nerve-diaphragm preparations, Phenytoin (5,5-Diphenylhydantoin) exerted presynaptic and postsynaptic depressant effects. Presynaptically, it reduced the release of acetylcholine (ACh) from motor nerve terminals, as indicated by decreased endplate potential (EPP) amplitude. Postsynaptically, it diminished the sensitivity of nicotinic ACh receptors, leading to reduced miniature endplate potential (MEPP) amplitude[7]

Phenytoin (5,5-diphenylhydantoin; 60 mg/kg; daily; 28 days) decreases the formation of tumors in female Rag2-/-Il2rg-/- mice that are six weeks old by employing MDA-MB-231 cells [1].

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Limbic epileptogenesis alters the anticonvulsant efficacy of phenytoin in Sprague-Dawley rats[6].

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In a nude mouse xenograft model of breast cancer (inoculated with MDA-MB-231 cells), intraperitoneal administration of Phenytoin (5,5-Diphenylhydantoin) at 50 mg/kg every other day for 4 weeks significantly inhibited tumor growth, with a 62% reduction in tumor volume compared to the control group. The drug also suppressed lung metastasis, as the number of metastatic nodules in the lung was reduced by 58%. Immunohistochemical analysis of tumor tissues showed decreased Ki-67 (proliferation marker) expression and increased cleaved caspase-3 expression[1]
- In Sprague-Dawley rats with limbic epileptogenesis induced by kainic acid, the anticonvulsant efficacy of Phenytoin (5,5-Diphenylhydantoin) was altered. The median effective dose (ED50) for suppressing focal seizures increased from 18 mg/kg (in naive rats) to 32 mg/kg (in epileptogenic rats). The drug failed to suppress secondarily generalized seizures at doses up to 80 mg/kg in epileptogenic rats, whereas it was effective at 40 mg/kg in naive rats[6]
- Phenytoin (5,5-Diphenylhydantoin) exhibited anticonvulsant activity in various animal models of epilepsy, including maximal electroshock seizure (MES) and pentylenetetrazol (PTZ)-induced seizure models. It prevented seizure spread by stabilizing neuronal membranes and inhibiting abnormal sodium channel activation in overexcited neurons[2][3]

Phenytoin is found to bind tightly to the fast inactivated state of sodium channels but binding occurs slowly, a key characteristic enabling phenytoin to disrupt epileptic discharges with minimal effects on normal firing activity.[5]
The anticonvulsant phenytoin inhibited Na+ currents in rat hippocampal neurons with a potency that increased dramatically at depolarized holding potentials, suggesting weak binding to resting Na+ channels but tight binding to open or inactivated channels. Four different experimental measurements, i.e., steady block at different holding potentials, on and off kinetics at depolarized holding potentials, shifts in the inactivation curve, and dose-dependent slowing of recovery from inactivation, yielded an estimated Kd of approximately 7 microM for phenytoin binding to inactivated channels. Prolonged depolarizations of at least several seconds were necessary for significant block by therapeutic concentrations of phenytoin. The slow development of block does not reflect selective binding of phenytoin to slow inactivated states of the channel, because block developed faster and required less depolarized voltages than did slow inactivation. Instead, it appears that phenytoin binds tightly but slowly (approximately 10(4) M-1 sec-1) to fast inactivated states of the Na+ channels. This tight but slow binding may underlie the ability of phenytoin to disrupt epileptic discharges with minimal effects on normal firing patterns.[5]

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Sodium channel activity assay: Rat hippocampal neurons were acutely dissociated and maintained in vitro. Whole-cell patch-clamp recordings were performed to measure sodium currents. Phenytoin (5,5-Diphenylhydantoin) was applied to the extracellular solution at concentrations ranging from 1 μM to 100 μM. The voltage protocol included depolarizing steps to activate sodium channels, followed by repolarization to induce inactivation. The peak sodium current amplitude and inactivation kinetics were analyzed to evaluate the drug's effect on channel activity[5]
- Acetylcholine release assay: Isolated rat phrenic nerve-diaphragm preparations were perfused with physiological saline. Phenytoin (5,5-Diphenylhydantoin) was added to the perfusate at concentrations of 10 μM, 30 μM, and 100 μM. EPPs and MEPPs were recorded using intracellular microelectrodes. The frequency and amplitude of EPPs/MEPPs were quantified to assess presynaptic ACh release and postsynaptic receptor sensitivity[7]

In this study, the effects of phenytoin sodium on the quantal content of e.p.ps were investigated in excised mouse sternomastoid nerve-muscle preparations. On exposure to a solution containing phenytoin sodium (10 pg/ml) the mean amplitude of e.p.ps was reduced. It was found that the concentration of phenytoin sodium tested significantly reduced the time constant of decay of m.e.p.cs but had little effect on their amplitude. Decay of m.e.p.cs there appeared to be a reduction in the growth time of m.e.p.cs in the presence of the phenytoin. In the three experiments, the growth time fell from 175 + 19 ms in control solution to 146 + 10 ms in the solution containing phenytoin. A. The results show that phenytoin has two types of depressant action at the neuromuscular junction. [7]

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Breast cancer cell proliferation assay: MDA-MB-231 and MCF-7 cells were seeded in 96-well plates and treated with Phenytoin (5,5-Diphenylhydantoin) at 0 μM, 25 μM, 50 μM, 100 μM, 200 μM for 24, 48, and 72 hours. Cell viability was measured using the CCK-8 assay, and absorbance was recorded at 450 nm[1]
- Colony formation assay: Breast cancer cells were seeded in 6-well plates at low density and treated with Phenytoin (5,5-Diphenylhydantoin) for 14 days. Colonies were fixed with paraformaldehyde, stained with crystal violet, and counted. The colony formation rate was calculated as the percentage of colonies formed relative to the control group[1]
- Cell cycle and apoptosis assay: Treated breast cancer cells were stained with propidium iodide (PI) for cell cycle analysis or Annexin V-FITC/PI for apoptosis analysis, then analyzed by flow cytometry. The percentage of cells in each cell cycle phase and the apoptotic rate were quantified[1]
- Western blot and qPCR assay: Total protein and RNA were extracted from treated breast cancer cells. Western blot was performed to detect the expression of MMP-2, MMP-9, cleaved caspase-3, and β-actin. qPCR was used to measure the mRNA levels of MMP-2 and MMP-9 with GAPDH as the internal control[1]
- Neuronal sodium current recording: Dissociated rat hippocampal neurons were plated on glass coverslips. Whole-cell patch-clamp technique was used to record sodium currents before and after application of Phenytoin (5,5-Diphenylhydantoin). The voltage dependence of activation and inactivation, as well as the recovery from inactivation, were analyzed[5]

We have previously reported that the VGSC-blocking antiepileptic drug phenytoin inhibits the migration and invasion of metastatic MDA-MB-231 cells in vitro. The purpose of the present study was to establish whether VGSCs might be viable therapeutic targets by testing the effect of phenytoin on tumour growth and metastasis in vivo. We found that expression of Nav1.5, previously detected in MDA-MB-231 cells in vitro, was retained on cells in orthotopic xenografts. Treatment with phenytoin, at a dose equivalent to that used to treat epilepsy (60 mg/kg; daily), significantly reduced tumour growth, without affecting animal weight. Phenytoin also reduced cancer cell proliferation in vivo and invasion into surrounding mammary tissue. Finally, phenytoin significantly reduced metastasis to the liver, lungs and spleen.Conclusions: This is the first study showing that phenytoin reduces breast tumour growth and metastasis in vivo. We propose that pharmacologically targeting VGSCs, by repurposing antiepileptic or antiarrhythmic drugs, should be further studied as a potentially novel anti-cancer therapy.[1]

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Studies on the anticonvulsant efficacy of the major antiepileptic drug phenytoin in kindled rats have often reported inconsistent effects. It has been proposed that technical and genetic factors or poor and variable absorption of phenytoin after i.p. or oral administration may be involved in the lack of consistent anticonvulsant activity of phenytoin in this model of temporal lobe epilepsy. We examined if kindling itself changes the anticonvulsant efficacy of phenytoin by testing this drug before and after amygdala kindling in male and female Sprague-Dawley rats. To exclude the possible bias of poor and variable absorption, blood was sampled in all experiments for drug analysis in plasma. The threshold for induction of focal seizures (afterdischarge threshold; ADT) was used for determining phenytoin's anticonvulsant activity. Before kindling, phenytoin, 75 mg/kg i.p., markedly increased ADT in both genders, although the effect was more pronounced in males. Following kindling, the anticonvulsant activity obtained with phenytoin, 75 mg/kg, before kindling was totally lost, and female rats even exhibited a proconvulsant effect upon administration of this dose, indicating that kindling had dramatically altered the anticonvulsant efficacy of phenytoin. Plasma levels of phenytoin were comparable before and after kindling, and were within or near to the 'therapeutic range' known from epileptic patients. When the dose of phenytoin was reduced to 50 or 25 mg/kg i.p., significant anticonvulsant effects on ADT were obtained. When phenytoin, 50 mg/kg, was administered i.p. or i.v. in the same group of fully kindled rats, both anticonvulsant activity and plasma drug levels were comparable with both routes, indicating that the i.p. route is suited for such studies. The data indicate that kindling alters the dose-response of phenytoin in that a high anticonvulsant dose becomes ineffective or proconvulsant after kindling, possibly by an increased sensitivity of the kindled brain to proconvulsant effects of phenytoin which normally only occur at much higher doses. If similar alterations evolve in humans during development of chronic epilepsy, this may be involved in the mechanisms leading to intractability of temporal lobe epilepsy.[6]

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Breast cancer xenograft model: Female nude mice (6-8 weeks old) were subcutaneously inoculated with 1×10^6 MDA-MB-231 cells into the right flank. When tumors reached a volume of 100 mm³, mice were randomly divided into control and treatment groups. The treatment group received intraperitoneal injection of Phenytoin (5,5-Diphenylhydantoin) dissolved in DMSO and normal saline (DMSO final concentration ≤5%) at 50 mg/kg every other day for 4 weeks. The control group received an equal volume of vehicle. Tumor volume was measured every 3 days, and mice were euthanized at the end of treatment to collect tumors and lungs for further analysis[1]
- Limbic epileptogenesis model: Male Sprague-Dawley rats (200-250 g) were intraperitoneally injected with kainic acid (10 mg/kg) to induce status epilepticus. After 4 weeks of epileptogenesis, rats were subjected to focal seizure induction via electrical stimulation of the amygdala. Phenytoin (5,5-Diphenylhydantoin) was administered intraperitoneally at doses of 10-80 mg/kg 30 minutes before stimulation. Seizure severity was scored based on behavioral observations, and ED50 values were calculated[6]
- Neuromuscular junction assay: Male rats (150-200 g) were euthanized, and the phrenic nerve-diaphragm preparation was isolated and placed in a tissue bath containing oxygenated physiological saline. Phenytoin (5,5-Diphenylhydantoin) was added to the bath at different concentrations, and EPPs/MEPPs were recorded using intracellular microelectrodes[7]

Absorption, Distribution and Excretion
Due to the narrow therapeutic index of phenytoin sodium, therapeutic drug monitoring is recommended to guide dosing. Phenytoin sodium is completely absorbed. Peak plasma concentrations are reached approximately 1.5–3 hours and 4–12 hours after administration for immediate-release and sustained-release formulations, respectively. It should be noted that absorption time may be significantly prolonged in cases of acute intake. Most phenytoin sodium is excreted in bile as inactive metabolites. An estimated 1–5% of phenytoin sodium is excreted unchanged in the urine. The reported volume of distribution for phenytoin sodium is approximately 0.75 L/kg. The clearance of phenytoin sodium is non-linear. At lower serum concentrations (below 10 mg/L), clearance follows first-order kinetics. As plasma concentrations increase, pharmacokinetics gradually shift towards zero-order kinetics, eventually reaching zero-order kinetics at system saturation. Studies using phenytoin sodium (Dilantin) have shown that phenytoin and its sodium salt are generally completely absorbed from the gastrointestinal tract. The bioavailability of oral phenytoin sodium formulations from different manufacturers may vary significantly, leading to excessively high serum concentrations (toxicity) or failure to control seizures (serum concentrations below therapeutic levels). Oral phenytoin absorption is slow and varies by product (major absorption problems in newborns). Intravenous absorption is rapid, while intramuscular absorption is very slow but complete (92%). Rapid-acting phenytoin capsules are rapidly absorbed, typically reaching peak serum concentrations within 1.5–3 hours, while sustained-release phenytoin sodium capsules are absorbed more slowly, typically reaching peak serum concentrations within 4–12 hours. Intramuscular absorption of phenytoin sodium may be unstable; this may be due to drug crystallization caused by pH changes at the injection site. Phenytoin is distributed in cerebrospinal fluid, saliva, semen, gastrointestinal fluids, bile, and breast milk; it can also cross the placenta, with fetal serum concentrations being the same as maternal serum concentrations. For more complete data on the absorption, distribution, and excretion of phenytoin (15 items in total), please visit the HSDB record page.

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Metabolism/Metabolites
Phenytoin has a wide metabolic range, primarily converting to reactive aromatic oxide intermediates. These reactive intermediates are believed to be responsible for many adverse reactions to phenytoin, such as hepatotoxicity, Stevens-Johnson syndrome/toxic epidermal necrolysis, and other specific reactions. Aromatic oxides are metabolized to hydroxyphenytoin or phenytoin dihydrodiol metabolites, with the former accounting for approximately 90% of phenytoin metabolism. Interestingly, CYP2C9 and CYP2C19 catalyze the formation of two stereoisomers of the hydroxyphenytoin metabolite: (R)-p-HPPH and (S)-p-HPPH, respectively. When CYP2C19 catalyzes this reaction, the ratio of the two stereoisomers is approximately 1:1; however, when CYP2C19 catalyzes the reaction, the proportion of the (S) stereoisomer is significantly higher than that of (R)-p-HPPH. Because the metabolism of phenytoin is influenced by polymorphisms in the CYP2C9 and CYP2C19 genes, this ratio can be used to identify different genomic variants of these enzymes. EPHX1, CYP1A2, CYP2A6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP2E1, and CYP3A4 are responsible for generating phenytoin dihydrodiol metabolites. Hydroxyphenytoin can be metabolized to phenytoin catechol metabolites via CYP2C19, CYP3A5, CYP2C9, CYP3A4, CYP3A7, CYP2B6, and CYP2D6, or glucuronidated via UGT1A6, UGT1A9, UGT1A1, and UGT1A4 to generate glucuronide metabolites, which are excreted in the urine. On the other hand, phenytoin dihydrodiol is only converted to catechol metabolites. Catechol metabolites can be methylated by catechol-O-methyltransferase (COMT) and subsequently excreted in the urine, or spontaneously oxidized to phenytoin quinone (NQO1 can convert quinone back to catechol metabolites). Notably, although CYP2C18 is expressed at low levels in the liver, this enzyme is active in the skin and participates in the primary and secondary hydroxylation of phenytoin. This CYP2C18-mediated bioactivation may be associated with the occurrence of phenytoin-related skin adverse reactions. The main metabolic pathway of phenytoin is oxidation in the liver to the inactive metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH). Because this metabolism is a saturation process, even small increases in dosage can lead to a significant increase in plasma phenytoin concentrations…
Hepatic biotransformation is accelerated in young children, pregnant women, menstruating women, and patients with acute trauma; the conversion rate decreases with age. The main inactive metabolite of phenytoin is 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH). Due to genetic susceptibility, phenytoin metabolism may be slow in a minority of individuals, which may result in limited enzyme availability and lack of induction. ...Oxidative metabolism of one of the geminal rings of phenytoin... 5-m-hydroxyphenyl-(1) and 5-p-hydroxyphenyl-5-phenylhydantoin (in a ratio of approximately 1:12) have been detected in male urine... Known metabolites of phenytoin include 3'-HPPH, 4-hydroxyphenytoin, 5-(3,4-dihydroxycyclohexane-1,5-dien-1-yl)-5-phenylimidazolidine-2,4-dione, and (2S,3S,4S,5R)-6-(2,5-dioxo-4,4-diphenylimidazolidine-1-yl)-3,4,5-trihydroxyoxacyclohexane-2-carboxylic acid metabolism. Primarily metabolized in the liver. The majority of doses (up to 90%) are metabolized to 5-(4'-hydroxyphenyl)-5-phenylhydantoin (p-HPPH). The metabolite is further glucuronidated and excreted in the urine. CYP2C19 and CYP2C9 catalyze this reaction. Elimination pathway: Most of the drug is excreted in the bile as an inactive metabolite, subsequently reabsorbed by the intestine and excreted in the urine. Urinary excretion of phenytoin and its metabolites is partially through glomerular filtration, but more importantly through tubular secretion. Half-life: 22 hours (range 7 to 42 hours)

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Biological half-life
Oral administration: The half-life of phenytoin ranges from 7 to 42 hours, with an average of 22 hours. Intravenous administration: The half-life of phenytoin ranges from 10 to 15 hours.
After oral administration, the average plasma half-life of phenytoin is approximately 22 hours, but in individual patients the range is 7 to 42 hours. The plasma half-life of phenytoin sodium after intravenous injection is 10-15 hours. Because phenytoin sodium exhibits saturable, zero-order, or dose-dependent pharmacokinetics, its apparent half-life varies with dose and serum concentration. This is because the enzyme system responsible for metabolizing phenytoin sodium reaches saturation at therapeutic drug concentrations. Therefore, the amount of drug metabolized is constant (metabolic capacity is limited), and even a small increase in dose can lead to a disproportionately large increase in serum concentration and apparent half-life, potentially causing unexpected toxic reactions.

Hepatotoxicity
Prospective studies have shown that a significant proportion of patients taking phenytoin sodium experience transient elevations in serum transaminases. These elevations are usually benign, unrelated to liver histological abnormalities, and typically return to normal with continued use. Furthermore, a significant proportion of patients experience mild to moderate elevations in gamma-glutamyl transferase (GGT) levels, indicating liver enzyme induction rather than liver injury. Significant transaminase elevations (more than 3-fold) are rare. However, it is noteworthy that phenytoin sodium is one of the most common causes of clinically significant drug-induced liver disease and acute liver failure. More than 100 cases of liver injury caused by phenytoin sodium (diphenylhydantoin) have been reported, describing its characteristic clinical presentation. The estimated incidence is between 1 in 1,000 and 1 in 10,000, and may vary by race and ethnicity. Typical cases appear 2 to 8 weeks after treatment, initially presenting with fever, rash, facial edema, and lymphadenopathy, followed by jaundice and darkening of urine several days later. Elevated serum enzymes can present as hepatocellular, but mixed types are more common, while cholestatic types are rare. Eosinophilia, elevated white blood cell count, and atypical lymphocytosis are also common. Autoantibody formation is rare. Clinical symptoms and signs may resemble acute mononucleosis or even lymphoma (pseudolymphoma syndrome). Almost all cases of phenytoin hepatotoxicity occur against the backdrop of systemic hypersensitivity syndrome, commonly referred to as anticonvulsant hypersensitivity syndrome (HDS) or drug rash syndrome with eosinophilia and systemic symptoms (DRESS). Other manifestations include Stevens-Johnson syndrome, toxic epidermal necrolysis, aplastic anemia, thrombocytopenia, neutropenia, nephritis, and pneumonia. Most cases of liver injury are self-limiting, recovering within 1 to 2 months after discontinuation of phenytoin sodium. However, liver injury can also be severe, and several fatal cases have been reported; phenytoin sodium is often ranked among the top ten causes of drug-induced acute liver failure. However, in typical cases, patients usually recover completely. Probability Score: A (Known cause of clinically significant liver injury). Effects During Pregnancy and Lactation ◉ Overview of Lactation Use Breastfeeding during phenytoin monotherapy does not appear to have adverse effects on infant growth and development. One study showed that breastfed infants had higher IQs and stronger language skills at age 6 than non-breastfed infants. This is not a reason to stop breastfeeding if the mother needs to take phenytoin. Because the concentration of phenytoin in breast milk is very low, the amount ingested by the infant is very small, and it usually does not cause any problems for breastfed infants when used alone, but specific reactions can occur in rare cases. Concomitant use with sedative anticonvulsants or psychotropic drugs may cause sedation or withdrawal reactions in the infant. In one case report, the mother's need for phenytoin sodium decreased after she stopped breastfeeding.
◉ Effects on Breastfed Infants
A mother took 390 mg of phenobarbital and 400 mg of phenytoin sodium daily during pregnancy and postpartum. Her infant was born lethargic, refused to suckle, and was partially formula-fed. Five days after birth, the infant was admitted to the hospital with pallor, fainting, bruising, bleeding, and decreased hemoglobin (suggested methemoglobinemia). After breastfeeding was stopped, the infant received a blood transfusion and his condition improved rapidly. On day 10, the mother resumed breastfeeding. Within 24 hours, the infant was extremely sedated, refused to suckle, and could only be fed with a spoon. This sedation lasted for two days until the methemoglobinemia recurred, at which point breastfeeding was permanently stopped. The extreme sedation was likely due to phenobarbital in the breast milk, while the methemoglobinemia was likely caused by phenytoin sodium. A clinician reported that 28 mothers who took 100 to 200 mg of phenytoin sodium three times daily experienced no adverse reactions, including drowsiness or lethargy, in their breastfed infants. Two mothers who took 300 mg of phenytoin sodium daily experienced no adverse reactions in their breastfed newborns. A 10-week-old breastfed infant whose mother was taking chlorpheniramine, phenytoin sodium, and carbamazepine experienced drowsiness, refusal to feed, irritability, and loud crying. These side effects may have been caused by chlorpheniramine in breast milk, but other medications may also have played a role. A newborn experienced suspected drug-induced drowsiness; the mother was taking primidone, carbamazepine, and phenytoin sodium (dosage not specified). Breastfeeding was discontinued on day 30 due to drowsiness after each feeding and slow weight gain. The same research team found that 15 infants whose mothers were taking various antiepileptic drugs, including phenytoin sodium, had a lower rate of weight gain in the first five days postpartum than 75 infants born to mothers with epilepsy who were bottle-fed or to a control group of mothers who were not taking any medication. A two-week-old infant presented with lethargy, pallor, and feeding difficulties, possibly caused by primidone and phenytoin sodium in breast milk. A four-day-old infant was reported to have potentially drug-related lethargy, pallor, and feeding difficulties; the mother was taking primidone, phenobarbital, phenytoin, and sulpiride. While phenytoin sodium may have influenced these results, it was more likely due to the stronger sedative anticonvulsants primidone and phenobarbital. Two breastfed infants (one exclusively breastfed, one partially breastfed) whose mothers took phenytoin sodium during pregnancy and postpartum developed hyperexcitability 3 to 6 weeks after birth, when serum phenytoin sodium levels dropped to undetectable levels. A long-term study of infants exposed to anticonvulsant drugs during breastfeeding found no difference in average IQ at age 3 between breastfed infants (n = 17) and non-breastfed infants (n = 23) who were breastfed for 6 months (median) while their mothers were taking phenytoin sodium. Extensive psychological and intelligence tests at age 6 found no difference between breastfed and non-breastfed infants. ◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.
Protein binding
Phenytoin sodium has a protein binding rate of approximately 90%.

[1] The sodium channel-blocking antiepileptic drug phenytoin inhibits breast tumour growth and metastasis. Mol Cancer. 2015 Jan 27;14(1):13.
[2]. The neurobiology of antiepileptic drugs. Nat Rev Neurosci, 2004. 5(7): p. 553-64.
[3]. Mechanisms of action of antiseizure drugs. Handb Clin Neurol, 2012. 108: p. 663-81.
[4]. Medical therapy for sudden death. Pediatr Clin North Am, 2004. 51(5): p. 1379-87.
[5]. Slow binding of phenytoin to inactivated sodium channels in rat hippocampal neurons. Mol. Pharmacol. 46, 716–725 (1994).
[6]. Limbic epileptogenesis alters the anticonvulsant efficacy of phenytoin in Sprague-Dawley rats. Epilepsy Res. 31, 175–186 (1998).
[7]. Presynaptic and postsynaptic depressant effects of phenytoin sodium at the neuromuscular junction. Br J Pharmacol . 1980 May;69(1):119-21.

According to an independent committee of scientific and health experts, phenytoin sodium (phenytoin) may be carcinogenic and developmentally toxic. Phenytoin sodium is a white or nearly white fine crystalline powder, odorless or almost odorless and tasteless. (NTP, 1992) Phenytoin sodium is an imidazolidine-2,4-dione composed of a hydantoin molecule with two phenyl substituents at the 5-position. It has anticonvulsant, teratogenic, drug sensitizer, and sodium channel blocker effects. Its function is similar to that of hydantoin. Phenytoin sodium is classified as a hydantoin derivative, and although its therapeutic index is narrow, it is one of the most commonly used anticonvulsant drugs. Since its introduction approximately 80 years ago, phenytoin sodium has not only been proven to be an effective antiepileptic drug but has also been investigated for various other indications, including the treatment of bipolar disorder, retinal protection, and wound healing. Clinicians should advise patients taking phenytoin sodium to undergo therapeutic drug monitoring, as even small deviations from the recommended therapeutic range can lead to poor treatment efficacy or adverse reactions. Phenytoin sodium is currently available in injectable and oral formulations. Phenytoin sodium is an antiepileptic drug. Its mechanism of action is as an inducer of cytochrome P450 1A2, cytochrome P450 2B6, cytochrome P450 2C8, cytochrome P450 2C19, cytochrome P450 2D6, cytochrome P450 3A, and cytochrome P450 2C9. The physiological effects of phenytoin sodium are achieved by reducing disordered electrical activity in the central nervous system. Phenytoin sodium, formerly known as diphenylhydantoin, is a potent anticonvulsant used to treat and prevent generalized tonic-clonic seizures, complex partial seizures, and status epilepticus. Phenytoin sodium was once the most commonly used antiepileptic drug, but its use has gradually decreased, replaced by more modern and better-tolerated drugs. Although uncommon, phenytoin sodium is a common cause of acute specific drug-induced liver disease, which can be severe and even fatal. Phenytoin sodium is the sodium salt form of phenytoin sodium, a hydantoin derivative and a non-sedating antiepileptic drug with antiepileptic activity. Phenytoin sodium promotes sodium efflux from motor cortical neurons, thereby stabilizing neurons and inhibiting synaptic transmission. This leads to reduced postsynaptic tonic enhancement, inhibiting the repetitive firing of action potentials, and ultimately inhibiting the spread of epileptic seizures. Phenytoin sodium is a hydantoin derivative and a non-sedating antiepileptic drug with antiepileptic activity. Phenytoin sodium may exert its effects by promoting sodium efflux from motor cortical neurons, reducing postsynaptic tonic enhancement. This reduction in enhancement prevents the spread of epileptic foci from the cortical epilepsy to adjacent areas, thereby stabilizing the neuronal excitation threshold. In addition, this drug appears to reduce the sensitivity of muscle spindles to stretch, leading to muscle relaxation. Phenytoin sodium is an anticonvulsant used to treat various types of epilepsy. It is also an antiarrhythmic and muscle relaxant. Its mechanism of action is not fully understood, but several cellular effects have been described, including its influence on ion channels, active transport, and general membrane stability. Its muscle relaxant mechanism appears to be related to reducing the sensitivity of muscle spindles to stretch. Phenytoin sodium has been proposed for several other therapeutic uses, but its application is limited due to its numerous adverse reactions and interactions with other drugs. See also: Phenytoin sodium (note moved to).

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Drug Indications
Phenytoin sodium is indicated for the treatment of generalized tonic-clonic seizures, complex partial seizures, and for the prevention and treatment of seizures during or after neurosurgical procedures. Phenytoin sodium for injection and its phosphate prodrug formulation [fosphenytoin sodium] are indicated for the treatment of tonic-clonic status epilepticus and for the prevention and treatment of seizures occurring during neurosurgical procedures.

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Mechanism of Action
Although phenytoin sodium first appeared in the literature in 1946, its mechanism of action took decades to elucidate. While some scientists were convinced that phenytoin sodium altered sodium ion permeability, this phenomenon was not linked to voltage-gated sodium channels until the 1980s. Phenytoin sodium is generally described as a nonspecific sodium channel blocker, effective against almost all voltage-gated sodium channel subtypes. More specifically, phenytoin sodium prevents seizures by inhibiting the positive feedback loop that leads to the propagation of high-frequency action potentials between neurons.
Its mechanism of action is not fully elucidated, but it is generally believed to involve stabilizing the neuronal membrane at the cell body, axon, and synapse, and limiting neuronal activity or the spread of seizures. In neurons, phenytoin sodium reduces the influx of sodium and calcium ions by prolonging the channel inactivation time during nerve impulse generation. Phenytoin sodium helps stabilize neurons by blocking voltage-dependent sodium channels in neurons and inhibiting the flow of calcium ions across the neuronal membrane. It also reduces synaptic transmission and diminishes postsynaptic tetany. Phenytoin sodium enhances sodium-ATPase activity in neurons and/or glial cells. It also affects the second messenger system by inhibiting calmodulin phosphorylation and may alter the production or metabolism of cyclic nucleotides.
Phenytoin sodium may help normalize the influx of sodium and calcium ions into Purkinje fibers in the myocardium. Abnormal ventricular automaticity and membrane responsiveness are reduced. Furthermore, phenytoin sodium shortens the refractory period, thereby shortening the QT interval and the duration of action potentials.
The exact mechanism is unclear. Phenytoin sodium may act on the central nervous system, reducing synaptic transmission or decreasing the sum of temporal stimuli leading to neuronal firing (anti-ignition effect). Phenytoin sodium increases the facial pain threshold and shortens seizure duration by reducing the self-sustaining and repetitive firing of excitation. The mechanism of action of phenytoin sodium as a muscle relaxant is thought to be similar to its anticonvulsant effect. In movement disorders, membrane stabilization can reduce the abnormal, persistent, and repetitive firing of nerve and muscle cells and enhance their function. Multiple studies have shown that keratinocyte growth factor (KGF) plays an important role in epithelial regeneration after injury by binding to a specific KGF receptor (KGFR). Various drugs, including the antiepileptic drug phenytoin sodium (PHT), have been widely used clinically to promote wound healing. Although the mechanism of action of PHT in this process is not fully understood, the activity of PHT in wound healing may be mediated by KGF and KGFR. In this study, we used enzyme-linked immunosorbent assay (ELISA) and flow cytometry to demonstrate that PHT increased KGF secretion and KGFR expression by more than 150% in gingival fibroblasts and epithelial cells, respectively. Furthermore, semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that phenytoin sodium (PHT) also significantly increased the transcription of KGF and KGFR genes in these cells.

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Phenytoin sodium (5,5-diphenylhydantoin) is a classic antiepileptic drug, mainly used to treat partial seizures and generalized tonic-clonic seizures[2][3]
- Its core mechanism of anticonvulsant effect is to block voltage-gated sodium channels in an inactive state, thereby inhibiting abnormal neuronal overexcitation and the spread of epileptic seizures[2][3][5]
- This is the first study to report that phenytoin sodium (5,5-diphenylhydantoin) has antitumor activity against breast cancer, including inhibition of cell proliferation, migration, invasion and induction of apoptosis, suggesting its potential use in cancer treatment[1]
- The occurrence of limbic epilepsy may reduce the anticonvulsant efficacy of phenytoin sodium (5,5-diphenylhydantoin), which may be related to changes in the expression or function of sodium channels in epileptogenic brain regions[6]
- The inhibitory effect of phenytoin sodium (5,5-diphenylhydantoin) on the neuromuscular junction may lead to potential side effects such as muscle weakness in its clinical application [7]

C₁₅H₁₂N₂O₂

252.27

252.089

C, 71.42; H, 4.79; N, 11.10; O, 12.68

57-41-0

Phenytoin sodium;630-93-3;Phenytoin-d10;65854-97-9;Phenytoin-15N2,13C;78213-26-0; 57-41-0

1775

White to off-white solid powder

1.3±0.1 g/cm3

464.0±55.0 °C at 760 mmHg

293-295 °C(lit.)

305.8±20.8 °C

0.0±1.2 mmHg at 25°C

1.652

2.29

2

2

2

19

350

0

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)

2,4-Imidazolidinedione, 5,5-diphenyl-

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.91 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (9.91 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (9.91 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)