What is the mechanism of phenytoin?

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 Names

Dilantin, Phenytek

Generic NamePhenytoinDrugBank Accession NumberDB00252Background

Phenytoin 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 approvedStructure

WeightAverage: 252.268
Monoisotopic: 252.089877638 Chemical FormulaC15H12N2O2Synonyms

• 5,5-Diphenyl-imidazolidine-2,4-dione
• 5,5-diphenylimidazolidine-2,4-dione
• 5,5-diphenyltetrahydro-1H-2,4-imidazoledione
• 5,5-Diphenyltetrahydro-1H-2,4-imidazoledione
• Diphenylhydantoin
• Fenitoina
• Phentytoin
• Phenytoin
• Phenytoine
• Phenytoinum

External IDs Indication

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

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Associated ConditionsContraindications & Blackbox Warnings

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Pharmacodynamics

Phenytoin 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 action

Although 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

Absorption

Given 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 distribution

The volume of distribution of phenytoin is reported to be approximately 0.75 L/kg.11

Protein binding

Phenytoin 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

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Route of elimination

The 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-life

Oral 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

Clearance

The 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 Effects

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Toxicity

The 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 Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails

Cytochrome P450 2C9	CYP2C9*3	(C;C) / (A;C)	C Allele	Effect Directly Studied	Patients with this genotype have reduced metabolism of phenytoin.	Details
HLA class I histocompatibility antigen, B-15 alpha chain	HLA-B*15:02	Not Available	HLA-B*15	ADR Directly Studied	The presence of this genotype in HLA-B is associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis when treated with phenytoin.	Details
Cytochrome P450 2C19	CYP2C19*2A	Not Available	681G>A	ADR Inferred	Poor drug metabolizer, risk of drug toxicity.	Details
Cytochrome P450 2C19	CYP2C19*2B	Not Available	681G>A	ADR Inferred	Poor drug metabolizer, risk of drug toxicity.	Details
Cytochrome P450 2C19	CYP2C19*3	Not Available	636G>A	ADR Inferred	Poor drug metabolizer, risk of drug toxicity.	Details
Cytochrome P450 2C19	CYP2C19*4	Not Available	1A>G	ADR Inferred	Poor drug metabolizer, risk of drug toxicity.	Details
Cytochrome P450 2C19	CYP2C19*5	Not Available	1297C>T	ADR Inferred	Poor drug metabolizer, risk of drug toxicity.	Details
Cytochrome P450 2C19	CYP2C19*6	Not Available	395G>A	ADR Inferred	Poor drug metabolizer, risk of drug toxicity.	Details
Cytochrome P450 2C19	CYP2C19*7	Not Available	19294T>A	ADR Inferred	Poor drug metabolizer, risk of drug toxicity.	Details
Cytochrome P450 2C19	CYP2C19*22	Not Available	557G>C / 991A>G	ADR Inferred	Poor drug metabolizer, risk of drug toxicity.	Details
Cytochrome P450 2C19	CYP2C19*24	Not Available	99C>T / 991A>G  … show all	ADR Inferred	Poor drug metabolizer, risk of drug toxicity.	Details
Cytochrome P450 2C19	CYP2C19*35	Not Available	12662A>G	ADR Inferred	Poor drug metabolizer, risk of drug toxicity.	Details
Cytochrome P450 2C9	CYP2C9*2	Not Available	430C>T	ADR Inferred	Poor drug metabolizer, risk of drug toxicity. Consider lower dose.	Details
Cytochrome P450 2C9	CYP2C9*3	Not Available	1075A>C	ADR Inferred	Poor drug metabolizer, risk of drug toxicity. Consider lower dose.	Details
Cytochrome P450 2C9	CYP2C9*4	Not Available	1076T>C	ADR Inferred	Poor drug metabolizer, risk of drug toxicity. Consider lower dose.	Details
Cytochrome P450 2C9	CYP2C9*5	Not Available	1080C>G	ADR Inferred	Poor drug metabolizer, risk of drug toxicity. Consider lower dose.	Details
Cytochrome P450 2C9	CYP2C9*8	Not Available	449G>A	ADR Inferred	Poor drug metabolizer, risk of drug toxicity. Consider lower dose.	Details
Cytochrome P450 2C9	CYP2C9*11	Not Available	1003C>T	ADR Inferred	Poor drug metabolizer, risk of drug toxicity. Consider lower dose.	Details
Cytochrome P450 2C9	CYP2C9*12	Not Available	1465C>T	ADR Inferred	Poor drug metabolizer, risk of drug toxicity. Consider lower dose.	Details
Cytochrome P450 2C9	CYP2C9*13	Not Available	269T>C	ADR Inferred	Poor drug metabolizer, risk of drug toxicity. Consider lower dose.	Details
Cytochrome P450 2C9	CYP2C9*14	Not Available	374G>A	ADR Inferred	Poor drug metabolizer, risk of drug toxicity. Consider lower dose.	Details
Cytochrome P450 2C9	CYP2C9*16	Not Available	895A>G	ADR Inferred	Poor drug metabolizer, risk of drug toxicity. Consider lower dose.	Details
Cytochrome P450 2C9	CYP2C9*18	Not Available	1075A>C / 1190A>C  … show all	ADR Inferred	Poor drug metabolizer, risk of drug toxicity. Consider lower dose.	Details
Cytochrome P450 2C9	CYP2C9*26	Not Available	389C>G	ADR Inferred	Poor drug metabolizer, risk of drug toxicity. Consider lower dose.	Details
Cytochrome P450 2C9	CYP2C9*28	Not Available	641A>T	ADR Inferred	Poor drug metabolizer, risk of drug toxicity. Consider lower dose.	Details
Cytochrome P450 2C9	CYP2C9*30	Not Available	1429G>A	ADR Inferred	Poor drug metabolizer, risk of drug toxicity. Consider lower dose.	Details
Cytochrome P450 2C9	CYP2C9*33	Not Available	395G>A	ADR Inferred	Poor drug metabolizer, risk of drug toxicity. Consider lower dose.	Details
Cytochrome P450 2C9	CYP2C9*6	Not Available	818delA	ADR Inferred	Poor drug metabolizer, risk of drug toxicity. Consider lower dose.	Details
Cytochrome P450 2C9	CYP2C9*15	Not Available	485C>A	ADR Inferred	Poor drug metabolizer, risk of drug toxicity. Consider lower dose.	Details
Cytochrome P450 2C9	CYP2C9*25	Not Available	353_362delAGAAATGGAA	ADR Inferred	Poor drug metabolizer, risk of drug toxicity. Consider lower dose.	Details
Cytochrome P450 2C9	CYP2C9*35	Not Available	374G>T / 430C>T	ADR Inferred	Poor drug metabolizer, risk of drug toxicity. Consider lower dose.	Details
Cytochrome P450 2C9	CYP2C9*6	Not Available	818delA	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Cytochrome P450 2C9	CYP2C9*15	Not Available	485C>A	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Cytochrome P450 2C9	CYP2C9*25	Not Available	353_362delAGAAATGGAA	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Cytochrome P450 2C9	CYP2C9*35	Not Available	374G>T / 430C>T	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Cytochrome P450 2C9	CYP2C9*2	Not Available	430C>T	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Cytochrome P450 2C9	CYP2C9*4	Not Available	1076T>C	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Cytochrome P450 2C9	CYP2C9*5	Not Available	1080C>G	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Cytochrome P450 2C9	CYP2C9*8	Not Available	449G>A	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Cytochrome P450 2C9	CYP2C9*11	Not Available	1003C>T	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Cytochrome P450 2C9	CYP2C9*12	Not Available	1465C>T	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Cytochrome P450 2C9	CYP2C9*13	Not Available	269T>C	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Cytochrome P450 2C9	CYP2C9*14	Not Available	374G>A	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Cytochrome P450 2C9	CYP2C9*16	Not Available	895A>G	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Cytochrome P450 2C9	CYP2C9*18	Not Available	1075A>C / 1190A>C  … show all	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Cytochrome P450 2C9	CYP2C9*26	Not Available	389C>G	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Cytochrome P450 2C9	CYP2C9*28	Not Available	641A>T	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Cytochrome P450 2C9	CYP2C9*30	Not Available	1429G>A	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Cytochrome P450 2C9	CYP2C9*33	Not Available	395G>A	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details

Drug Interactions

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.

DrugInteraction

1,2-Benzodiazepine	The metabolism of 1,2-Benzodiazepine can be increased when combined with Phenytoin.
Abacavir	The metabolism of Abacavir can be increased when combined with Phenytoin.
Abametapir	The serum concentration of Phenytoin can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Phenytoin can be increased when combined with Abatacept.
Abemaciclib	The metabolism of Abemaciclib can be increased when combined with Phenytoin.
Abiraterone	The metabolism of Abiraterone can be increased when combined with Phenytoin.
Abrocitinib	The metabolism of Abrocitinib can be increased when combined with Phenytoin.
Acalabrutinib	The metabolism of Acalabrutinib can be increased when combined with Phenytoin.
Acarbose	The therapeutic efficacy of Acarbose can be decreased when used in combination with Phenytoin.
Acebutolol	The metabolism of Phenytoin can be decreased when combined with Acebutolol.

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Food Interactions

• Avoid alcohol. Alcohol may increase or decrease serum levels of phenytoin.
• Take separate from antacids. Take at least 2 hours before or after antacids. Taking this medication with antacids can reduce absorption.
• Take with food. Food reduces irritation and increases bioavailability.

UNII6158TKW0C5CAS number57-41-0InChI KeyCXOFVDLJLONNDW-UHFFFAOYSA-NInChI

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 Name

5,5-diphenylimidazolidine-2,4-dione

SMILES

O=C1NC(=O)C(N1)(C1=CC=CC=C1)C1=CC=CC=C1

Manufacturers

• Parke davis div warner lambert co
• Actavis mid atlantic llc
• Taro pharmaceutical industries ltd
• Vistapharm inc
• Wockhardt eu operations (swiss) ag
• Pfizer pharmaceuticals ltd
• Lannett co inc
• Amneal pharmaceuticals ny llc
• Barr laboratories inc
• Mylan pharmaceuticals inc
• Pliva inc
• Sun pharmaceutical industries ltd
• Wockhardt ltd
• Wockhardt usa inc
• Watson laboratories inc
• Pharmeral inc
• Ivax pharmaceuticals inc sub teva pharmaceuticals usa
• Parke davis pharmaceutical research div warner lambert co
• App pharmaceuticals llc
• Baxter healthcare corp
• Hikma farmaceutica (portugal) sa
• Hospira inc
• Marsam pharmaceuticals llc
• Pharmaforce inc
• Smith and nephew solopak div smith and nephew
• Solopak medical products inc
• Warner chilcott div warner lambert co

Packagers

• Actavis Group
• Amerisource Health Services Corp.
• Amneal Pharmaceuticals
• Apotheca Inc.
• A-S Medication Solutions LLC
• Barr Pharmaceuticals
• Baxter International Inc.
• Bilcare Inc.
• Bryant Ranch Prepack
• C.O. Truxton Inc.
• Caraco Pharmaceutical Labs
• Cardinal Health
• Carlisle Laboratories Inc.
• Comprehensive Consultant Services Inc.
• Coupler Enterprises Inc.
• Direct Dispensing Inc.
• Dispensing Solutions
• Diversified Healthcare Services Inc.
• General Injectables and Vaccines Inc.
• Heartland Repack Services LLC
• Hikma Pharmaceuticals
• Hospira Inc.
• JHP Pharmaceuticals LLC
• Kaiser Foundation Hospital
• Lake Erie Medical and Surgical Supply
• Major Pharmaceuticals
• Medisca Inc.
• Murfreesboro Pharmaceutical Nursing Supply
• Mylan
• Neuman Distributors Inc.
• Nucare Pharmaceuticals Inc.
• Palmetto Pharmaceuticals Inc.
• PCA LLC
• PD-Rx Pharmaceuticals Inc.
• Pfizer Inc.
• Pharmaceutical Packaging Center
• Pharmedix
• Physicians Total Care Inc.
• Prasco Labs
• Precision Dose Inc.
• Preferred Pharmaceuticals Inc.
• Prepackage Specialists
• Prepak Systems Inc.
• Rebel Distributors Corp.
• Redpharm Drug
• Remedy Repack
• Resource Optimization and Innovation LLC
• Sandhills Packaging Inc.
• Southwood Pharmaceuticals
• Spectrum Pharmaceuticals
• Stat Rx Usa
• Sun Pharmaceutical Industries Ltd.
• Taro Pharmaceuticals USA
• Tya Pharmaceuticals
• UDL Laboratories
• Vangard Labs Inc.
• Vistapharm Inc.
• Warner Chilcott Co. Inc.
• Warner Lambert Company LLC
• West-Ward Pharmaceuticals
• Wockhardt Ltd.
• Xactdose Inc.

Dosage FormsFormRouteStrength

Injection, solution	Parenteral	250 MG/5ML
Injection	Intravenous	50 mg/ml
Capsule	Oral	30 mg/1
Capsule, extended release	Oral	100.02 mg
Capsule, extended release	Oral	30 mg/1
Injection	Parenteral	50 mg/1mL
Suspension	Oral	125.00 mg/5ml
Tablet, chewable	Oral	50 mg/1
Liquid	Intramuscular; Intravenous	250 mg / 5 mL
Injection, solution	Intramuscular; Intravenous	250 MG/5ML
Capsule	Oral
Suspension	Oral	125 mg / 5 mL
Suspension	Oral	30 mg / 5 mL
Tablet, coated	Oral	100 MG
Suspension	Oral	2.5 g
Capsule, coated	Oral	0.1 g
Suspension	Oral	0.75 g
Solution	Parenteral	100 mg
Suspension	Oral	750 mg
Injection, solution	Parenteral
Injection	Parenteral
Tablet	Oral
Injection, solution	Intravenous
Injection, solution	Intramuscular; Intravenous
Capsule, coated	Oral	100 mg
Solution	Intramuscular; Intravenous	250 mg
Injection, solution	Parenteral	50 MG/ML
Injection, solution
Solution	Intravenous	100 mg
Solution	Intravenous	250 mg
Injection	Parenteral	50 mg
Solution	Intramuscular	0.25 g
Tablet	Oral
Tablet	Oral	100 mg
Injection	Intravenous
Capsule, extended release	Oral	300 mg/1
Suspension	Oral	100 mg/4mL
Suspension	Oral	125 mg/5mL
Capsule	Oral	100 mg/1
Tablet, film coated	Oral	100 MG
Capsule	Oral
Capsule, extended release	Oral	100 mg/1
Capsule, extended release	Oral	200 mg/1
Injection
Injection	Intramuscular; Intravenous	250 mg/5mL
Injection	Intramuscular; Intravenous	50 mg/1mL
Injection	Intravenous	50 mg/1mL
Injection, solution	Intramuscular; Intravenous	50 mg/1mL
Liquid	Intramuscular; Intravenous	50 mg / mL
Solution	Intramuscular; Intravenous	50 mg / mL
Capsule	Oral	100 mg
Injection, solution		50 mg/1ml
Tablet	Oral	50 mg
Capsule, extended release	Oral	100 mg
Capsule	Oral	30 mg
Solution		50 mg/1ml

PricesUnit descriptionCostUnit

Dilantin 125 mg/5ml Suspension 237ml Bottle	69.28USD	bottle
Phenytoin Sodium 50 mg/ml	2.64USD	ml
Phenytek 300 mg capsule	1.47USD	capsule
Phenytoin sod ext 300 mg capsule	1.2USD	capsule
Phenytoin sodium powder	1.16USD	g
Phenytek 200 mg capsule	0.98USD	capsule
Phenytoin 50 mg/ml ampul	0.96USD	ml
Phenytoin sod ext 200 mg capsule	0.8USD	capsule
Phenytoin 50 mg/ml vial	0.67USD	ml
Phenytoin 100 mg/2 ml vial	0.6USD	ml
Dilantin Infatabs 50 mg Chew Tabs	0.6USD	tab
Dilantin 100 mg capsule	0.51USD	capsule
Phenytoin 100 mg/4 ml susp	0.48USD	ml
Dilantin 30 mg capsule	0.46USD	capsule
Phenytoin 250 mg/5 ml vial	0.45USD	ml
Dilantin 50 mg infatab	0.44USD	each
Dilantin 100 mg kapseal	0.39USD	each
Dilantin 30 mg kapseal	0.39USD	each
Phenytoin Sodium Extended 100 mg capsule	0.36USD	capsule
Phenytoin sod ext 100 mg capsule	0.34USD	capsule
Phenytoin powder	0.23USD	g
Phenytoin 125 mg/5ml Suspension	0.15USD	ml
Dilantin Infatabs 50 mg Chewable Tablet	0.08USD	tablet
Dilantin 100 mg Capsule	0.08USD	capsule
Dilantin 30 mg Capsule	0.06USD	capsule
Dilantin-125 25 mg/ml Suspension	0.05USD	ml
Dilantin-30 6 mg/ml Suspension	0.04USD	ml
Taro-Phenytoin 25 mg/ml Suspension	0.03USD	ml

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

PatentsNot Available

KindProteinOrganismHumansPharmacological action

No

Actions

Substrate

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

1. Levy RH: Cytochrome P450 isozymes and antiepileptic drug interactions. Epilepsia. 1995;36 Suppl 5:S8-13. [Article]
2. Tate SK, Depondt C, Sisodiya SM, Cavalleri GL, Schorge S, Soranzo N, Thom M, Sen A, Shorvon SD, Sander JW, Wood NW, Goldstein DB: Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin. Proc Natl Acad Sci U S A. 2005 Apr 12;102(15):5507-12. Epub 2005 Apr 1. [Article]
3. Komatsu T, Yamazaki H, Asahi S, Gillam EM, Guengerich FP, Nakajima M, Yokoi T: Formation of a dihydroxy metabolite of phenytoin in human liver microsomes/cytosol: roles of cytochromes P450 2C9, 2C19, and 3A4. Drug Metab Dispos. 2000 Nov;28(11):1361-8. [Article]
4. Lynch T, Price A: The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 2007 Aug 1;76(3):391-6. [Article]
5. van der Weide J, Steijns LS, van Weelden MJ, de Haan K: The effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirement. Pharmacogenetics. 2001 Jun;11(4):287-91. [Article]
6. Johannessen SI, Landmark CJ: Antiepileptic drug interactions - principles and clinical implications. Curr Neuropharmacol. 2010 Sep;8(3):254-67. doi: 10.2174/157015910792246254. [Article]
7. Flockhart Table of Drug Interactions [Link]
8. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
9. Get to Know an Enzyme: CYP2C9 [File]

KindProteinOrganismHumansPharmacological action

No

Actions

Substrate

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

1. Levy RH: Cytochrome P450 isozymes and antiepileptic drug interactions. Epilepsia. 1995;36 Suppl 5:S8-13. [Article]
2. Komatsu T, Yamazaki H, Asahi S, Gillam EM, Guengerich FP, Nakajima M, Yokoi T: Formation of a dihydroxy metabolite of phenytoin in human liver microsomes/cytosol: roles of cytochromes P450 2C9, 2C19, and 3A4. Drug Metab Dispos. 2000 Nov;28(11):1361-8. [Article]
3. Giancarlo GM, Venkatakrishnan K, Granda BW, von Moltke LL, Greenblatt DJ: Relative contributions of CYP2C9 and 2C19 to phenytoin 4-hydroxylation in vitro: inhibition by sulfaphenazole, omeprazole, and ticlopidine. Eur J Clin Pharmacol. 2001 Apr;57(1):31-6. [Article]
4. Flockhart Table of Drug Interactions [Link]
5. Cytochrome P450 2C19 by Straight Healthcare [Link]
6. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]

KindProteinOrganismHumansPharmacological action

No

Actions

Substrate

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

1. Rendic S: Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448. [Article]
2. Backman JT, Filppula AM, Niemi M, Neuvonen PJ: Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions. Pharmacol Rev. 2016 Jan;68(1):168-241. doi: 10.1124/pr.115.011411. [Article]
3. Ferguson SS, Chen Y, LeCluyse EL, Negishi M, Goldstein JA: Human CYP2C8 is transcriptionally regulated by the nuclear receptors constitutive androstane receptor, pregnane X receptor, glucocorticoid receptor, and hepatic nuclear factor 4alpha. Mol Pharmacol. 2005 Sep;68(3):747-57. Epub 2005 Jun 2. [Article]

KindProteinOrganismHumansPharmacological action

No

Actions

Substrate

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

1. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [Article]
2. Flockhart Table of Drug Interactions [Link]

KindProteinOrganismHumansPharmacological action

No

Actions

Substrate

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

1. Ohno Y, Hisaka A, Ueno M, Suzuki H: General framework for the prediction of oral drug interactions caused by CYP3A4 induction from in vivo information. Clin Pharmacokinet. 2008;47(10):669-80. doi: 10.2165/00003088-200847100-00004. [Article]
2. Zhou SF: Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Curr Drug Metab. 2008 May;9(4):310-22. [Article]
3. Purkins L, Wood N, Ghahramani P, Love ER, Eve MD, Fielding A: Coadministration of voriconazole and phenytoin: pharmacokinetic interaction, safety, and toleration. Br J Clin Pharmacol. 2003 Dec;56 Suppl 1:37-44. doi: 10.1046/j.1365-2125.2003.01997.x. [Article]
4. Zhou SF, Xue CC, Yu XQ, Li C, Wang G: Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther Drug Monit. 2007 Dec;29(6):687-710. doi: 10.1097/FTD.0b013e31815c16f5. [Article]
5. Hole K, Wollmann BM, Nguyen C, Haslemo T, Molden E: Comparison of CYP3A4-Inducing Capacity of Enzyme-Inducing Antiepileptic Drugs Using 4beta-Hydroxycholesterol as Biomarker. Ther Drug Monit. 2018 Aug;40(4):463-468. doi: 10.1097/FTD.0000000000000518. [Article]
6. Johannessen SI, Landmark CJ: Antiepileptic drug interactions - principles and clinical implications. Curr Neuropharmacol. 2010 Sep;8(3):254-67. doi: 10.2174/157015910792246254. [Article]
7. Flockhart Table of Drug Interactions [Link]
8. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]

KindProteinOrganismHumansPharmacological action

No

Actions

Substrate

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

1. Usui T, Saitoh Y, Komada F: Induction of CYP3As in HepG2 cells by several drugs. Association between induction of CYP3A4 and expression of glucocorticoid receptor. Biol Pharm Bull. 2003 Apr;26(4):510-7. doi: 10.1248/bpb.26.510. [Article]
2. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [Article]

KindProteinOrganismHumansPharmacological action

No

Actions

Substrate

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

1. Usui T, Saitoh Y, Komada F: Induction of CYP3As in HepG2 cells by several drugs. Association between induction of CYP3A4 and expression of glucocorticoid receptor. Biol Pharm Bull. 2003 Apr;26(4):510-7. doi: 10.1248/bpb.26.510. [Article]
2. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [Article]

KindProteinOrganismHumansPharmacological action

No

Actions

Inhibitor

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

1. Funakoshi M: The effect of phenytoin on the corticoidogenesis in the mitochondria and the endoplasmic reticulum of bovine adrenal cortex. Shika Kiso Igakkai Zasshi. 1989 Feb;31(1):95-101. [Article]

KindProteinOrganismHumansPharmacological action

No

Actions

Substrate

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

1. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [Article]
2. Hirashima R, Michimae H, Takemoto H, Sasaki A, Kobayashi Y, Itoh T, Tukey RH, Fujiwara R: Induction of the UDP-Glucuronosyltransferase 1A1 during the Perinatal Period Can Cause Neurodevelopmental Toxicity. Mol Pharmacol. 2016 Sep;90(3):265-74. doi: 10.1124/mol.116.104174. Epub 2016 Jul 13. [Article]
3. Interactions [Link]

KindProteinOrganismHumansPharmacological action

No

Actions

Substrate

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

1. Kostrubsky SE, Sinclair JF, Strom SC, Wood S, Urda E, Stolz DB, Wen YH, Kulkarni S, Mutlib A: Phenobarbital and phenytoin increased acetaminophen hepatotoxicity due to inhibition of UDP-glucuronosyltransferases in cultured human hepatocytes. Toxicol Sci. 2005 Sep;87(1):146-55. doi: 10.1093/toxsci/kfi211. Epub 2005 Jun 2. [Article]
2. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [Article]

KindProteinOrganismHumansPharmacological action

No

Actions

Substrate

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

1. Kostrubsky SE, Sinclair JF, Strom SC, Wood S, Urda E, Stolz DB, Wen YH, Kulkarni S, Mutlib A: Phenobarbital and phenytoin increased acetaminophen hepatotoxicity due to inhibition of UDP-glucuronosyltransferases in cultured human hepatocytes. Toxicol Sci. 2005 Sep;87(1):146-55. doi: 10.1093/toxsci/kfi211. Epub 2005 Jun 2. [Article]
2. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [Article]
3. Yamanaka H, Nakajima M, Hara Y, Katoh M, Tachibana O, Yamashita J, Yokoi T: Urinary excretion of phenytoin metabolites, 5-(4'-hydroxyphenyl)-5-phenylhydantoin and its O-glucuronide in humans and analysis of genetic polymorphisms of UDP-glucuronosyltransferases. Drug Metab Pharmacokinet. 2005 Apr;20(2):135-43. doi: 10.2133/dmpk.20.135. [Article]

KindProteinOrganismHumansPharmacological action

No

Actions

Inducer

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

1. Johannessen SI, Landmark CJ: Antiepileptic drug interactions - principles and clinical implications. Curr Neuropharmacol. 2010 Sep;8(3):254-67. doi: 10.2174/157015910792246254. [Article]

KindProteinOrganismHumansPharmacological action

No

Actions

Substrate

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

1. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [Article]

KindProteinOrganismHumansPharmacological action

No

Actions

Substrate

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

1. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [Article]

KindProteinOrganismHumansPharmacological action

No

Actions

Substrate

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

1. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [Article]

KindProteinOrganismHumansPharmacological action

No

Actions

Substrate

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

1. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [Article]

KindProteinOrganismHumansPharmacological action

No

Actions

Substrate

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

1. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [Article]

KindProteinOrganismHumansPharmacological action

No

Actions

Substrate

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

1. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [Article]

KindProteinOrganismHumansPharmacological action

No

Actions

Substrate

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

1. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [Article]

KindProteinOrganismHumansPharmacological action

No

Actions

Substrate

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

1. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [Article]

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

1. Chen J, Ohnmacht C, Hage DS: Studies of phenytoin binding to human serum albumin by high-performance affinity chromatography. J Chromatogr B Analyt Technol Biomed Life Sci. 2004 Sep 25;809(1):137-45. [Article]
2. Ohnmacht CM, Chen S, Tong Z, Hage DS: Studies by biointeraction chromatography of binding by phenytoin metabolites to human serum albumin. J Chromatogr B Analyt Technol Biomed Life Sci. 2006 May 19;836(1-2):83-91. Epub 2006 Apr 18. [Article]
3. Co M, Lo A: Effect of albumin on phenytoin concentration: are we flogging a dead horse? Can J Hosp Pharm. 2011 Jul;64(4):293. doi: 10.4212/cjhp.v64i4.1051. [Article]

KindProteinOrganismHumansPharmacological action

No

Actions

Substrate

General FunctionSerine-type endopeptidase inhibitor activitySpecific FunctionMajor thyroid hormone transport protein in serum.Gene NameSERPINA7Uniprot IDP05543Uniprot NameThyroxine-binding globulinMolecular Weight46324.12 Da

1. Finucane JF, Griffiths RS: Effect of phenytoin therapy on thyroid function. Br J Clin Pharmacol. 1976 Dec;3(6):1041-4. doi: 10.1111/j.1365-2125.1976.tb00355.x. [Article]
2. EUTHYROX (levothyroxine sodium) tablets, for oral use - FDA Label [Link]
3. CYTOMEL (liothyronine) FDA label [File]

KindProteinOrganismHumansPharmacological action

Unknown

Actions

Inhibitor

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

1. Westholm DE, Stenehjem DD, Rumbley JN, Drewes LR, Anderson GW: Competitive inhibition of organic anion transporting polypeptide 1c1-mediated thyroxine transport by the fenamate class of nonsteroidal antiinflammatory drugs. Endocrinology. 2009 Feb;150(2):1025-32. doi: 10.1210/en.2008-0188. Epub 2008 Oct 9. [Article]
2. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [Article]

KindProteinOrganismHumansPharmacological action

Unknown

Actions

Substrate

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

1. Baltes S, Gastens AM, Fedrowitz M, Potschka H, Kaever V, Loscher W: Differences in the transport of the antiepileptic drugs phenytoin, levetiracetam and carbamazepine by human and mouse P-glycoprotein. Neuropharmacology. 2007 Feb;52(2):333-46. Epub 2006 Oct 10. [Article]
2. Luna-Tortos C, Fedrowitz M, Loscher W: Several major antiepileptic drugs are substrates for human P-glycoprotein. Neuropharmacology. 2008 Dec;55(8):1364-75. doi: 10.1016/j.neuropharm.2008.08.032. Epub 2008 Sep 11. [Article]
3. Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB: PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70. doi: 10.1097/FPC.0b013e32834aeedb. [Article]
4. Simon C, Stieger B, Kullak-Ublick GA, Fried M, Mueller S, Fritschy JM, Wieser HG, Pauli-Magnus C: Intestinal expression of cytochrome P450 enzymes and ABC transporters and carbamazepine and phenytoin disposition. Acta Neurol Scand. 2007 Apr;115(4):232-42. doi: 10.1111/j.1600-0404.2006.00761.x. [Article]

KindProteinOrganismHumansPharmacological action

Unknown

Actions

Substrate

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

1. Baltes S, Gastens AM, Fedrowitz M, Potschka H, Kaever V, Loscher W: Differences in the transport of the antiepileptic drugs phenytoin, levetiracetam and carbamazepine by human and mouse P-glycoprotein. Neuropharmacology. 2007 Feb;52(2):333-46. Epub 2006 Oct 10. [Article]
2. Potschka H, Fedrowitz M, Loscher W: Multidrug resistance protein MRP2 contributes to blood-brain barrier function and restricts antiepileptic drug activity. J Pharmacol Exp Ther. 2003 Jul;306(1):124-31. doi: 10.1124/jpet.103.049858. Epub 2003 Mar 27. [Article]
3. Simon C, Stieger B, Kullak-Ublick GA, Fried M, Mueller S, Fritschy JM, Wieser HG, Pauli-Magnus C: Intestinal expression of cytochrome P450 enzymes and ABC transporters and carbamazepine and phenytoin disposition. Acta Neurol Scand. 2007 Apr;115(4):232-42. doi: 10.1111/j.1600-0404.2006.00761.x. [Article]