Phenytoin blocks voltage-sensitive sodium channels in neurons. This action leads to a delay in neuronal electrical recovery from inactivation. [1] Phenytoin's inhibitory effect is dependent on the voltage and frequency of neural cell firing by selectively blocking the neurons that are firing at high frequency. Phenytoin prevents the electrical spread of a focus of irritable tissue from entering normal tissue. Phenytoin administration has been associated with toxic effects. Phenytoin toxicity depends on the route of administration, duration, exposure, and dosage. The route of administration is the most important determinant of toxicity. Phenytoin may be administered orally or intravenously. In addition, fosphenytoin (water-soluble phenytoin prodrug) may be administered intramuscularly. Phenytoin is a weak acid and has erratic GI absorption. Following ingestion, phenytoin precipitates in the stomach's acid environment; this characteristic is particularly important in the setting of an intentional overdose. Peak blood levels occur 3-12 hours following single dose ingestion, but absorption can be extended up to 2 weeks, especially in massive overdose. Oral exposures are associated predominantly with CNS symptoms. The parenteral form of phenytoin is dissolved in 40% propylene glycol and 10% ethanol and adjusted to a pH of 12; sodium hydroxide is added to maintain solubility. Extravasation of the solution may cause skin irritation or phlebitis. Phenytoin administered intravenously at a rate higher than 50 mg/min may cause hypotension and arrhythmias. These complications are believed to be secondary to the diluent, propylene glycol. However, cardiac toxicity was reported even after rapid administration of fosphenytoin that does not contain propylene glycol, suggesting intrinsic phenytoin cardiac toxicity. Orally administered phenytoin is rarely, if ever, associated with cardiac toxicity. Phenytoin has a small volume of distribution of 0.6 L/kg and is extensively bound to plasma proteins (90%). Blood levels of phenytoin reflect only total serum concentration of the drug. Only the free unbound phenytoin has biological activity. Because CNS tissue levels are higher than in serum, levels may underestimate CNS concentrations of phenytoin. [2] Population groups that are predisposed to elevated free phenytoin levels include neonates, elderly persons, and individuals with uremia, hypoalbuminemia (due to pregnancy, nephrotic syndrome, malignancy, malnutrition), or hyperbilirubinemia. These patients may exhibit signs of toxicity when drug levels are within the therapeutic range (see Lab Studies). Certain medications can interfere with phenytoin levels. Hepatic microsomal enzymes primarily metabolize phenytoin. Much of the drug is excreted in the bile as an inactive metabolite, which is then reabsorbed from the intestinal tract and ultimately excreted in the urine. Less than 5% of phenytoin is excreted unchanged in the urine. Individuals with impaired metabolic or excretory pathways may exhibit early signs of toxicity. Genetic polymorphism in the cytochrome enzymes that metabolize phenytoin may be responsible for variable rates of metabolism and thus susceptibility to toxicity, even in individuals taking appropriate doses. [3, 4] Phenytoin metabolism is dose dependent. Elimination follows first-order kinetics (fixed percentage of drug metabolized during a per unit time) at the low drug concentrations and zero-order kinetics (fixed amount of drug metabolized per unit time) at higher drug concentrations. This change in kinetics reflects the saturation of metabolic pathways. Thus, very small increments in dosage may result in adverse effects. Summary Phenytoin is an anticonvulsant drug used in the prophylaxis and control of various types of seizures. Brand NamesDilantin, Phenytek Generic NamePhenytoinDrugBank Accession NumberDB00252BackgroundPhenytoin is classified as a hydantoin derivative and despite its narrow therapeutic index, it is one of the most commonly used anticonvulsants.12,6,8 Since it's introduction about 80 years ago, phenytoin has not only been established as an effective anti-epileptic, but has also been investigated for several other indications such as bipolar disorder, retina protection, and wound healing.7,6 Clinicians are advised to initiate therapeutic drug monitoring in patients who require phenytoin since even small deviations from the recommended therapeutic range can lead to suboptimal treatment, or adverse effects.8,10 Both parenteral and oral formulations of phenytoin are available on the market.8 TypeSmall MoleculeGroupsApproved, Vet approvedStructureMonoisotopic: 252.089877638 Chemical FormulaC15H12N2O2Synonyms
Phenytoin is indicated to treat grand mal seizures, complex partial seizures, and to prevent and treat seizures during or following neurosurgery.14 Injectable phenytoin and Fosphenytoin, which is the phosphate ester prodrug formulation of phenytoin2, are indicated to treat tonic-clonic status epilepticus, and for the prevention and treatment of seizures occurring during neurosurgery.15 Reduce drug development failure rates Build, train, & validate machine-learning models Build, train, & validate predictive machine-learning models with structured datasets. Associated ConditionsContraindications & Blackbox WarningsAvoid life-threatening adverse drug events Improve clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more. Avoid life-threatening adverse drug events & improve clinical decision support. PharmacodynamicsPhenytoin is an anticonvulsant with a narrow therapeutic index.5 Although the recommended therapeutic range is cited to be between 10-20 mg/L, differences in albumin levels, genetics, comorbidities, and body composition can make achieving an ideal phenytoin dose challenging.5 For example, studies have confirmed that phenytoin metabolism is impacted by CYP2C9 genotype polymorphisms and possibly by CYP2C19 genotype polymorphisms (the latter has not been as extensively studied).5 It is worth nothing that although phenytoin is highly protein bound, only the fraction unbound is able to exert a pharmacological effect.17 Therefore, factors that reduce or increase the percentage of protein bound phenytoin (for example: concomitant administration of drugs that can cause displacement from protein binding sites) can have a marked impact on phenytoin therapy.4,17 Mechanism of actionAlthough phenytoin first appeared in the literature in 1946, it has taken decades for the mechanism of action to be more specifically elucidated.7 Although several scientists were convinced that phenytoin altered sodium permeability, it wasn’t until the 1980’s that this phenomenon was linked to voltage-gated sodium channels.7 Phenytoin is often described as a non-specific sodium channel blocker and targets almost all voltage-gated sodium channel subtypes.7 More specifically, phenytoin prevents seizures by inhibiting the positive feedback loop that results in neuronal propagation of high frequency action potentials.5,8,9 AbsorptionGiven its narrow therapeutic index, therapeutic drug monitoring is recommended to help guide dosing.8,10 Phenytoin is completely absorbed.8 Peak plasma concentration is attained approximately 1.5-3 hours, and 4-12 hours after administration of the immediate release formulation and the extended release formulation, respectively.3,8 It should be noted that absorption can be markedly prolonged in situations of acute ingestion.8 Volume of distributionThe volume of distribution of phenytoin is reported to be approximately 0.75 L/kg.11 Protein bindingPhenytoin is roughly 90% protein bound.4 Phenytoin is extensively metabolized and is first transformed into a reactive arene oxide intermediate.12 It is thought that this reactive intermediate is responsible for many undesirable phenytoin adverse effects such as hepatotoxicity, SJS/TEN, and other idiosyncratic reactions.12 The arene oxide is metabolized to either a hydroxyphenytoin or phenytoin dihydrodiol metabolite, although the former accounts for about 90% of phenytoin metabolism.12 Interestingly, two stereoisomers of the hydroxyphenytoin metabolite are formed by CYP2C9 and CYP2C19: (R)-p-HPPH and (S)-p-HPPH.12 When CYP2C19 catalyzes the reaction, the ratio of stereoisomers is roughly 1:1, whereas when CYP2C9 catalyzes the reaction, the ratio heavily favours the "S" stereoisomer.12 Since the metabolism of phenytoin is in part influenced by genetic polymorphisms of CYP2C9 and CYP2C19, this ratio can be utilized to identify different genomic variants of the enzymes.5,6,12 EPHX1, CYP1A2, CYP2A6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP2E1 and CYP3A4 are responsible for producing the phenytoin dihydrodiol metabolite.12 Hydroxyphenytoin can be metabolized by CYP2C19, CYP3A5, CYP2C9, CYP3A4, CYP3A7, CYP2B6 and CYP2D6 to a phenytoin catechol metabolite or undergo glucuronidation by UGT1A6, UGT1A9, UGT1A1, and UGT1A4 to a glucuronide metabolite that can be eliminated in the urine.12 On the other hand, the phenytoin dihydrodiol entity is only transformed to the catechol metabolite.12 The catechol metabolite can undergo methylation by COMT and be subsequently eliminated in the urine, or can spontaneously oxidize to a phenytoin quinone (NQO1 can transform the quinone back to the catechol metabolite).12 Of note, although CYP2C18 is poorly expressed in the liver, the enzyme is active in the skin and is involved in the primary and secondary hydroxylation of phenytoin.12,13 This CYP2C18 mediated bioactivation may be linked to the manifestation of adverse cutaneous drug reactions associated with phenytoin.12 Hover over products below to view reaction partners Route of eliminationThe majority of phenytoin is excreted as inactive metabolites in the bile.14,16 An estimated 1-5% of phenytoin is eliminated unchanged in the urine.8 Half-lifeOral administration: The half-life of phenytoin ranges from 7 to 42 hours, and is 22 hours on average.11,14 Intravenous administration: The half-life of phenytoin ranges from 10-15 hours.16 ClearanceThe clearance of phenytoin is non-linear.10 At lower serum concentrations (less than 10 mg/L), elimination is characterized by first order kinetics.3 As plasma concentrations increase, the kinetics shift gradually towards zero-order, and finally reach zero-order kinetics once the system is saturated.3 Adverse EffectsImprove decision support & research outcomes With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. Improve decision support & research outcomes with our structured adverse effects data. ToxicityThe experience of phenytoin toxicity is not limited to situations of acute ingestion, but may also occur due to drug interactions or due to physiological circumstances that impact serum albumin (ie. kidney disease) or drug metabolism.3 Other changes that may result in phenytoin toxicity include pregnancy, malnutrition and malignancy.3 Phenytoin toxicity most often affects the cardiovascular and nervous systems.3 The most common presentation of toxicity depends on the route of administration.3 Cardiovascular adverse effects are most commonly linked to intravenous phenytoin administration, whereas neurological adverse effects are more common with oral phenytoin administration.3 Neurotoxicity is usually dependent on serum concentrations.3 When concentrations range from 10-20 mg/L, mild nystagmus and lateral gaze may occur, while more significant nystagmus is associated with concentrations ranging from 20-30 mg/L.3 At concentrations of 30-40 mg/L, slurred speech, tremor, nausea, vomiting and ataxia have been reported.3 In more serious cases where serum levels range from 40-50 mg/L patients are at risk of lethargy, confusion and hyperactivity, and at levels beyond 50 mg/L, coma and seizures may occur.3 Phenytoin is classified as an antiarrhythmic and can cause SA and AV nodal blocks as well as dysrhythmias due to its effect on voltage-gated sodium channels.3 Further, since phenytoin is poorly soluble, the parenteral form is administered with propylene glycol, which is a cardiac depressant.3 The infusion rate of parenteral phenytoin should not exceed 50 mg per minute due to the risk of hypotension, bradycardia, and asystole.3 Treatment for phenytoin toxicity is non-specific and centres around supportive care.3 One dose of activated charcoal may be used to prevent phenytoin absorption in cases of acute ingestion.3 Although hemodialysis is moderately effective at removing phenytoin, it is not normally recommended due to the risks associated with the procedure, and the general effectiveness of supportive care.3 PathwaysPharmacogenomic Effects/ADRs
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
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) IUPAC Name5,5-diphenylimidazolidine-2,4-dione SMILESO=C1NC(=O)C(N1)(C1=CC=CC=C1)C1=CC=CC=C1
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only. PatentsNot AvailableKindProteinOrganismHumansPharmacological action No ActionsSubstrate Inhibitor Inducer General FunctionSteroid hydroxylase activitySpecific FunctionCytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...Gene NameCYP2C9Uniprot IDP11712Uniprot NameCytochrome P450 2C9Molecular Weight55627.365 Da
KindProteinOrganismHumansPharmacological action No ActionsSubstrate Inducer General FunctionSteroid hydroxylase activitySpecific FunctionResponsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...Gene NameCYP2C19Uniprot IDP33261Uniprot NameCytochrome P450 2C19Molecular Weight55930.545 Da
KindProteinOrganismHumansPharmacological action No ActionsSubstrate Inducer General FunctionSteroid hydroxylase activitySpecific FunctionCytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...Gene NameCYP2C8Uniprot IDP10632Uniprot NameCytochrome P450 2C8Molecular Weight55824.275 Da
KindProteinOrganismHumansPharmacological action No ActionsSubstrate Inducer General FunctionSteroid hydroxylase activitySpecific FunctionCytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...Gene NameCYP2B6Uniprot IDP20813Uniprot NameCytochrome P450 2B6Molecular Weight56277.81 Da
KindProteinOrganismHumansPharmacological action No ActionsSubstrate Inducer General FunctionVitamin d3 25-hydroxylase activitySpecific FunctionCytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...Gene NameCYP3A4Uniprot IDP08684Uniprot NameCytochrome P450 3A4Molecular Weight57342.67 Da
KindProteinOrganismHumansPharmacological action No ActionsSubstrate Inducer General FunctionOxygen bindingSpecific FunctionCytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...Gene NameCYP3A5Uniprot IDP20815Uniprot NameCytochrome P450 3A5Molecular Weight57108.065 Da
KindProteinOrganismHumansPharmacological action No ActionsSubstrate Inducer General FunctionOxygen bindingSpecific FunctionCytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...Gene NameCYP3A7Uniprot IDP24462Uniprot NameCytochrome P450 3A7Molecular Weight57525.03 Da
KindProteinOrganismHumansPharmacological action No ActionsInhibitor General FunctionSteroid 11-beta-monooxygenase activitySpecific FunctionHas steroid 11-beta-hydroxylase activity. In addition to this activity, the 18 or 19-hydroxylation of steroids and the aromatization of androstendione to estrone have also been ascribed to cytochro...Gene NameCYP11B1Uniprot IDP15538Uniprot NameCytochrome P450 11B1, mitochondrialMolecular Weight57572.44 Da
KindProteinOrganismHumansPharmacological action No ActionsSubstrate Inducer General FunctionSteroid bindingSpecific FunctionUDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...Gene NameUGT1A1Uniprot IDP22309Uniprot NameUDP-glucuronosyltransferase 1-1Molecular Weight59590.91 Da
KindProteinOrganismHumansPharmacological action No ActionsSubstrate Inhibitor General FunctionProtein homodimerization activitySpecific FunctionUDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 3 lacks trans...Gene NameUGT1A6Uniprot IDP19224Uniprot NameUDP-glucuronosyltransferase 1-6Molecular Weight60750.215 Da
KindProteinOrganismHumansPharmacological action No ActionsSubstrate Inhibitor General FunctionRetinoic acid bindingSpecific FunctionUDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans...Gene NameUGT1A9Uniprot IDO60656Uniprot NameUDP-glucuronosyltransferase 1-9Molecular Weight59940.495 Da
KindProteinOrganismHumansPharmacological action No ActionsInducer General FunctionOxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygenSpecific FunctionCytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...Gene NameCYP1A2Uniprot IDP05177Uniprot NameCytochrome P450 1A2Molecular Weight58293.76 Da
KindProteinOrganismHumansPharmacological action No ActionsSubstrate General FunctionSteroid hydroxylase activitySpecific FunctionExhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Const...Gene NameCYP2A6Uniprot IDP11509Uniprot NameCytochrome P450 2A6Molecular Weight56501.005 Da
KindProteinOrganismHumansPharmacological action No ActionsSubstrate General FunctionSteroid hydroxylase activitySpecific FunctionResponsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...Gene NameCYP2D6Uniprot IDP10635Uniprot NameCytochrome P450 2D6Molecular Weight55768.94 Da
KindProteinOrganismHumansPharmacological action No ActionsSubstrate General FunctionSteroid hydroxylase activitySpecific FunctionMetabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...Gene NameCYP2E1Uniprot IDP05181Uniprot NameCytochrome P450 2E1Molecular Weight56848.42 Da
KindProteinOrganismHumansPharmacological action No ActionsSubstrate General FunctionBiotransformation enzyme that catalyzes the hydrolysis of arene and aliphatic epoxides to less reactive and more water soluble dihydrodiols by the trans addition of water (By similarity). May play a role in the metabolism of endogenous lipids such as epoxide-containing fatty acids (PubMed:22798687).Specific FunctionCis-stilbene-oxide hydrolase activityGene NameEPHX1Uniprot IDP07099Uniprot NameEpoxide hydrolase 1Molecular Weight52948.48 Da
KindProteinOrganismHumansPharmacological action No ActionsSubstrate General FunctionProtein homodimerization activitySpecific FunctionUDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...Gene NameUGT1A4Uniprot IDP22310Uniprot NameUDP-glucuronosyltransferase 1-4Molecular Weight60024.535 Da
KindProteinOrganismHumansPharmacological action No ActionsSubstrate General FunctionO-methyltransferase activitySpecific FunctionCatalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like L-DOP...Gene NameCOMTUniprot IDP21964Uniprot NameCatechol O-methyltransferaseMolecular Weight30036.77 Da
KindProteinOrganismHumansPharmacological action No ActionsSubstrate General FunctionSuperoxide dismutase activitySpecific FunctionThe enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinons involved in detoxification pathways as well as in biosynthetic processes such as the vit...Gene NameNQO1Uniprot IDP15559Uniprot NameNAD(P)H dehydrogenase [quinone] 1Molecular Weight30867.405 Da
KindProteinOrganismHumansPharmacological action No ActionsSubstrate General FunctionSteroid hydroxylase activitySpecific FunctionCytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...Gene NameCYP2C18Uniprot IDP33260Uniprot NameCytochrome P450 2C18Molecular Weight55710.075 Da
KindProteinOrganismHumansPharmacological action Unknown General FunctionToxic substance bindingSpecific FunctionSerum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...Gene NameALBUniprot IDP02768Uniprot NameSerum albuminMolecular Weight69365.94 Da
KindProteinOrganismHumansPharmacological action No ActionsSubstrate General FunctionSerine-type endopeptidase inhibitor activitySpecific FunctionMajor thyroid hormone transport protein in serum.Gene NameSERPINA7Uniprot IDP05543Uniprot NameThyroxine-binding globulinMolecular Weight46324.12 Da
KindProteinOrganismHumansPharmacological action Unknown ActionsInhibitor General FunctionThyroid hormone transmembrane transporter activitySpecific FunctionMediates the Na(+)-independent high affinity transport of organic anions such as the thyroid hormones thyroxine (T4) and rT3. Other potential substrates, such as triiodothyronine (T3), 17-beta-gluc...Gene NameSLCO1C1Uniprot IDQ9NYB5Uniprot NameSolute carrier organic anion transporter family member 1C1Molecular Weight78695.625 Da
KindProteinOrganismHumansPharmacological action Unknown ActionsSubstrate General FunctionXenobiotic-transporting atpase activitySpecific FunctionEnergy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.Gene NameABCB1Uniprot IDP08183Uniprot NameMultidrug resistance protein 1Molecular Weight141477.255 Da
KindProteinOrganismHumansPharmacological action Unknown ActionsSubstrate General FunctionOrganic anion transmembrane transporter activitySpecific FunctionMediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter.Gene NameABCC2Uniprot IDQ92887Uniprot NameCanalicular multispecific organic anion transporter 1Molecular Weight174205.64 Da
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