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Identification
- Summary
Dofetilide is a class III antiarrhythmic drug used for the maintenance of normal sinus rhythm and cardioversion in cases of atrial fibrillation and atrial flutter.
- Brand Names
- Tikosyn
- Generic Name
- Dofetilide
- DrugBank Accession Number
- DB00204
- Background
Dofetilide is a class III antiarrhythmic agent that is approved by the Food and Drug Administration (FDA) for the maintenance of sinus rhythm in individuals prone to the formation of atrial fibrillation and flutter, and for the chemical cardioversion to sinus rhythm from atrial fibrillation and flutter.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Dofetilide (DB00204)
- Weight
- Average: 441.565
Monoisotopic: 441.139212369 - Chemical Formula
- C19H27N3O5S2
- Synonyms
- beta-((p-Methanesulfonamidophenethyl)methylamino)methanesulfono-p-phenetidide
- Dofetilida
- Dofetilide
- Dofetilidum
- External IDs
- UK-68,798
- UK-68798
Pharmacology
- Indication
For the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter [AF/AFl]) in patients with atrial fibrillation/atrial flutter of greater than one week duration who have been converted to normal sinus rhythm
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Maintenance of Normal sinus rhythm •••••••••••• ••••••••••• •••••• ••••••• Maintenance of Normal sinus rhythm •••••••••••• •••••••••••• ••••••••• •••••• •••••••••••• Management of Symptomatic atrial fibrillation •••••••••••• Management of Symptomatic atrial flutter •••••••••••• - Contraindications & Blackbox Warnings
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Dofetilide is an antiarrhythmic drug with Class III (cardiac action potential duration prolonging) properties and is indicated for the maintenance of normal sinus rhythm. Dofetilide increases the monophasic action potential duration in a predictable, concentration-dependent manner, primarily due to delayed repolarization. At concentrations covering several orders of magnitude, Dofetilide blocks only IKr with no relevant block of the other repolarizing potassium currents (e.g., IKs, IK1). At clinically relevant concentrations, Dofetilide has no effect on sodium channels (associated with Class I effect), adrenergic alpha-receptors, or adrenergic beta-receptors.
- Mechanism of action
The mechanism of action of Dofetilide is a blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current, IKr. This inhibition of potassium channels results in a prolongation of action potential duration and the effective refractory period of accessory pathways (both anterograde and retrograde conduction in the accessory pathway).
Target Actions Organism AVoltage-gated inwardly rectifying potassium channel KCNH2 inhibitorHumans APotassium channel subfamily K member 2 inhibitorHumans AATP-sensitive inward rectifier potassium channel 12 inhibitorHumans - Absorption
>90%
- Volume of distribution
- 3 L/kg
- Protein binding
60% -70%
- Metabolism
Hepatic
- Route of elimination
Not Available
- Half-life
10 hours
- Clearance
Not Available
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Not Available
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Dofetilide can be increased when it is combined with Abametapir. Abatacept The metabolism of Dofetilide can be increased when combined with Abatacept. Acalabrutinib The metabolism of Dofetilide can be decreased when combined with Acalabrutinib. Acebutolol Dofetilide may increase the arrhythmogenic activities of Acebutolol. Acetaminophen The metabolism of Dofetilide can be increased when combined with Acetaminophen. - Food Interactions
- Exercise caution with grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of dofetilide.
- Exercise caution with St. John's Wort. Dofetilide is partially metabolized by CYP3A4, and St. John's Wort is a CYP3A4 inducer, coadministration may reduce dofetilide serum levels.
- Take with or without food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Images
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Dofetilide Capsule 0.25 mg/1 Oral Greenstone LLC 2016-05-01 2021-03-31 US 
Dofetilide Capsule 0.125 mg/1 Oral Greenstone LLC 2016-05-01 2021-03-31 US Dofetilide Capsule 0.5 mg/1 Oral Greenstone LLC 2016-05-01 2021-03-31 US Tikosyn Capsule 0.25 mg/1 Oral Pfizer Laboratories Div Pfizer Inc 1999-10-01 Not applicable US 
Tikosyn Capsule 0.125 mg/1 Oral Avera McKennan Hospital 2016-06-28 Not applicable US - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Dofetilide Capsule 250 ug/1 Oral Sigmapharm Laboratories, LLC 2018-06-11 Not applicable US Dofetilide Capsule 0.5 mg/1 Oral Bionpharma Inc. 2018-04-11 Not applicable US Dofetilide Capsule 0.125 mg/1 Oral NorthStar Rx LLC 2018-06-18 2024-03-31 US Dofetilide Capsule 0.25 mg/1 Oral Liberty Bioscience LLC 2016-06-07 Not applicable US Dofetilide Capsule 0.25 mg/1 Oral VGYAAN Pharmaceuticals LLC 2021-07-31 Not applicable US
Categories
- ATC Codes
- C01BD04 — Dofetilide
- Drug Categories
- Amides
- Amines
- Antiarrhythmic agents
- Antiarrhythmics, Class III
- Cardiac Therapy
- Cardiovascular Agents
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Substrates
- Ethylamines
- Highest Risk QTc-Prolonging Agents
- Membrane Transport Modulators
- Narrow Therapeutic Index Drugs
- OCT2 Substrates
- OCT2 Substrates with a Narrow Therapeutic Index
- Potassium Channel Blockers
- QTc Prolonging Agents
- Sulfones
- Sulfur Compounds
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as sulfanilides. These are organic aromatic compounds containing a sulfanilide moiety, with the general structure RS(=O)(=O)NC1=CC=CC=C1.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Sulfanilides
- Direct Parent
- Sulfanilides
- Alternative Parents
- Phenethylamines / Phenoxy compounds / Phenol ethers / Aralkylamines / Alkyl aryl ethers / Organosulfonamides / Organic sulfonamides / Aminosulfonyl compounds / Trialkylamines / Organopnictogen compounds show 2 more
- Substituents
- Alkyl aryl ether / Amine / Aminosulfonyl compound / Aralkylamine / Aromatic homomonocyclic compound / Ether / Hydrocarbon derivative / Organic nitrogen compound / Organic oxide / Organic oxygen compound show 15 more
- Molecular Framework
- Aromatic homomonocyclic compounds
- External Descriptors
- tertiary amino compound, aromatic ether, sulfonamide (CHEBI:4681)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- R4Z9X1N2ND
- CAS number
- 115256-11-6
- InChI Key
- IXTMWRCNAAVVAI-UHFFFAOYSA-N
- InChI
- InChI=1S/C19H27N3O5S2/c1-22(13-12-16-4-6-17(7-5-16)20-28(2,23)24)14-15-27-19-10-8-18(9-11-19)21-29(3,25)26/h4-11,20-21H,12-15H2,1-3H3
- IUPAC Name
- N-[4-(2-{[2-(4-methanesulfonamidophenoxy)ethyl](methyl)amino}ethyl)phenyl]methanesulfonamide
- SMILES
- CN(CCOC1=CC=C(NS(C)(=O)=O)C=C1)CCC1=CC=C(NS(C)(=O)=O)C=C1
References
- Synthesis Reference
- US4959366
- General References
- Lenz TL, Hilleman DE: Dofetilide, a new class III antiarrhythmic agent. Pharmacotherapy. 2000 Jul;20(7):776-86. [Article]
- Lenz TL, Hilleman DE: Dofetilide: A new antiarrhythmic agent approved for conversion and/or maintenance of atrial fibrillation/atrial flutter. Drugs Today (Barc). 2000 Nov;36(11):759-71. [Article]
- Torp-Pedersen C, Moller M, Bloch-Thomsen PE, Kober L, Sandoe E, Egstrup K, Agner E, Carlsen J, Videbaek J, Marchant B, Camm AJ: Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl J Med. 1999 Sep 16;341(12):857-65. [Article]
- External Links
- Human Metabolome Database
- HMDB0014349
- KEGG Drug
- D00647
- KEGG Compound
- C07751
- PubChem Compound
- 71329
- PubChem Substance
- 46509127
- ChemSpider
- 64435
- BindingDB
- 50031720
- 49247
- ChEBI
- 4681
- ChEMBL
- CHEMBL473
- ZINC
- ZINC000000596731
- Therapeutic Targets Database
- DAP000495
- PharmGKB
- PA449389
- Guide to Pharmacology
- GtP Drug Page
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Dofetilide
- FDA label
- Download (1.45 MB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Completed Not Available Atrial Fibrillation 1 somestatus stop reason just information to hide Not Available Completed Treatment Atrial Fibrillation 1 somestatus stop reason just information to hide Not Available Recruiting Treatment Persistent Atrial Fibrillation (AF) 1 somestatus stop reason just information to hide Not Available Unknown Status Not Available Long QT Syndrome (LQTS) / Therapeutic Agent Toxicity 1 somestatus stop reason just information to hide 4 Completed Not Available Paroxysmal Atrial Fibrillation (PAF) 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Pfizer pharmaceuticals production corp ltd
- Packagers
- Pfizer Inc.
- Dosage Forms
Form Route Strength Capsule Oral 0.250 mg/1 Capsule Oral 0.500 mg/1 Capsule Oral 125 ug/1 Capsule Oral 250 ug/1 Capsule Oral 500 ug/1 Capsule Oral 0.125 mg/1 Capsule Oral 0.25 mg/1 Capsule Oral 0.5 mg/1 - Prices
Unit description Cost Unit Tikosyn 250 mcg capsule 3.64USD capsule Tikosyn 125 mcg capsule 3.63USD capsule Tikosyn 500 mcg capsule 3.61USD capsule DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US4959366 No 1990-09-25 2012-09-25 US US6124363 No 2000-09-26 2018-10-09 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source logP 2.1 Not Available - Predicted Properties
Property Value Source Water Solubility 0.0198 mg/mL ALOGPS logP 2.17 ALOGPS logP 0.24 Chemaxon logS -4.4 ALOGPS pKa (Strongest Acidic) 10.15 Chemaxon pKa (Strongest Basic) 8.99 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 6 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 104.81 Å2 Chemaxon Rotatable Bond Count 9 Chemaxon Refractivity 113.27 m3·mol-1 Chemaxon Polarizability 46.03 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9924 Blood Brain Barrier + 0.9179 Caco-2 permeable - 0.6257 P-glycoprotein substrate Substrate 0.6018 P-glycoprotein inhibitor I Inhibitor 0.6848 P-glycoprotein inhibitor II Non-inhibitor 0.7391 Renal organic cation transporter Non-inhibitor 0.7308 CYP450 2C9 substrate Non-substrate 0.7572 CYP450 2D6 substrate Non-substrate 0.9116 CYP450 3A4 substrate Substrate 0.6699 CYP450 1A2 substrate Non-inhibitor 0.6359 CYP450 2C9 inhibitor Non-inhibitor 0.5189 CYP450 2D6 inhibitor Non-inhibitor 0.7709 CYP450 2C19 inhibitor Inhibitor 0.544 CYP450 3A4 inhibitor Non-inhibitor 0.7715 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.6823 Ames test Non AMES toxic 0.6193 Carcinogenicity Non-carcinogens 0.6038 Biodegradation Not ready biodegradable 1.0 Rat acute toxicity 2.5430 LD50, mol/kg Not applicable hERG inhibition (predictor I) Strong inhibitor 0.8119 hERG inhibition (predictor II) Inhibitor 0.8258
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 221.4559268 predictedDarkChem Lite v0.1.0 [M-H]- 228.8388268 predictedDarkChem Lite v0.1.0 [M-H]- 197.56929 predictedDeepCCS 1.0 (2019) [M+H]+ 221.5667268 predictedDarkChem Lite v0.1.0 [M+H]+ 229.7354268 predictedDarkChem Lite v0.1.0 [M+H]+ 199.92729 predictedDeepCCS 1.0 (2019) [M+Na]+ 221.1060268 predictedDarkChem Lite v0.1.0 [M+Na]+ 228.8362268 predictedDarkChem Lite v0.1.0 [M+Na]+ 206.44478 predictedDeepCCS 1.0 (2019)
Targets
Build, predict & validate machine-learning models
Use our structured and evidence-based datasets to unlock newinsights and accelerate drug research.
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel (PubMed:10219239, PubMed:10753933, PubMed:10790218, PubMed:10837251, PubMed:11997281, PubMed:12063277, PubMed:18559421, PubMed:22314138, PubMed:22359612, PubMed:26363003, PubMed:27916661, PubMed:9230439, PubMed:9351446, PubMed:9765245). Channel properties are modulated by cAMP and subunit assembly (PubMed:10837251). Characterized by unusual gating kinetics by producing relatively small outward currents during membrane depolarization and large inward currents during subsequent repolarization which reflect a rapid inactivation during depolarization and quick recovery from inactivation but slow deactivation (closing) during repolarization (PubMed:10219239, PubMed:10753933, PubMed:10790218, PubMed:10837251, PubMed:11997281, PubMed:12063277, PubMed:18559421, PubMed:22314138, PubMed:22359612, PubMed:26363003, PubMed:27916661, PubMed:9230439, PubMed:9351446, PubMed:9765245). Channel properties are modulated by cAMP and subunit assembly (PubMed:10837251). Forms a stable complex with KCNE1 or KCNE2, and that this heteromultimerization regulates inward rectifier potassium channel activity (PubMed:10219239, PubMed:9230439)
- Specific Function
- delayed rectifier potassium channel activity
- Gene Name
- KCNH2
- Uniprot ID
- Q12809
- Uniprot Name
- Voltage-gated inwardly rectifying potassium channel KCNH2
- Molecular Weight
- 126653.52 Da
References
- Lees-Miller JP, Duan Y, Teng GQ, Duff HJ: Molecular determinant of high-affinity dofetilide binding to HERG1 expressed in Xenopus oocytes: involvement of S6 sites. Mol Pharmacol. 2000 Feb;57(2):367-74. [Article]
- Overholt JL, Ficker E, Yang T, Shams H, Bright GR, Prabhakar NR: HERG-Like potassium current regulates the resting membrane potential in glomus cells of the rabbit carotid body. J Neurophysiol. 2000 Mar;83(3):1150-7. [Article]
- Finlayson K, Pennington AJ, Kelly JS: [3H]dofetilide binding in SHSY5Y and HEK293 cells expressing a HERG-like K+ channel? Eur J Pharmacol. 2001 Feb 2;412(3):203-12. [Article]
- Finlayson K, Turnbull L, January CT, Sharkey J, Kelly JS: [3H]dofetilide binding to HERG transfected membranes: a potential high throughput preclinical screen. Eur J Pharmacol. 2001 Oct 26;430(1):147-8. [Article]
- Ficker E, Jarolimek W, Brown AM: Molecular determinants of inactivation and dofetilide block in ether a-go-go (EAG) channels and EAG-related K(+) channels. Mol Pharmacol. 2001 Dec;60(6):1343-8. [Article]
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
- Ficker E, Jarolimek W, Kiehn J, Baumann A, Brown AM: Molecular determinants of dofetilide block of HERG K+ channels. Circ Res. 1998 Feb 23;82(3):386-95. [Article]
- Kang J, Chen XL, Wang H, Ji J, Cheng H, Incardona J, Reynolds W, Viviani F, Tabart M, Rampe D: Discovery of a small molecule activator of the human ether-a-go-go-related gene (HERG) cardiac K+ channel. Mol Pharmacol. 2005 Mar;67(3):827-36. Epub 2004 Nov 17. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- K(+) channel that conducts voltage-dependent outward rectifying currents upon membrane depolarization. Voltage sensing is coupled to K(+) electrochemical gradient in an 'ion flux gating' mode where outward but not inward ion flow opens the gate. Converts to voltage-independent 'leak' conductance mode upon stimulation by various stimuli including mechanical membrane stretch, acidic pH, heat and lipids. Reversibly converts between a voltage-insensitive K(+) 'leak' channel and a voltage-dependent outward rectifying K(+) channel in a phosphorylation-dependent manner (By similarity) (PubMed:10321245, PubMed:10784345, PubMed:11319556, PubMed:23169818, PubMed:30573346, PubMed:38605031). Homo- and heterodimerizes to form functional channels with distinct regulatory and gating properties (By similarity). In trigeminal ganglia sensory neurons, the heterodimer of KCNK2/TREK-1 and KCNK18/TRESK inhibits neuronal firing and neurogenic inflammation by stabilizing the resting membrane potential at K(+) equilibrium potential as well as by regulating the threshold of action potentials and the spike frequency (By similarity). At trigeminal A-beta afferent nerves, the heterodimer of KCNK2/TREK-1 and KCNK4/TRAAK is mostly coexpressed at nodes of Ranvier where it conducts voltage-independent mechanosensitive and thermosensitive currents, allowing rapid action potential repolarization, high speed and high frequence saltatory conduction on myelinated nerves to ensure prompt sensory responses (By similarity). In hippocampal astrocytes, the heterodimer of KCNK2/TREK-1 and KCNK1/TWIK-1 allows passive K(+) conductance under basal conditions, but changes ion selectivity and becomes permeable to L-glutamate and Cl(-) ions upon binding to G-protein subunit GNG4 in stimulated astrocytes. Mediates rapid L-glutamate release in response to activation of G-protein-coupled receptors, such as F2R and CNR1 (By similarity). In hippocampal pyramidal neurons, the homodimer of KCNK2/TREK-1 contributes to gamma-aminobutyric acid (GABA) B-induced slow inhibitory postsynaptic potential. Associates with AKAP5 and Gs-protein-coupled receptor B2AR at postsynaptic dense bodies and converts to a leak channel no longer sensitive to stimulation by arachidonic acid, acidic pH or mechanical stress, nor inhibited by Gq-coupled receptors but still under the negative control of Gs-coupled receptors (By similarity). Permeable to other monovalent cations such as Rb(+) and Cs(+) (By similarity)
- Specific Function
- outward rectifier potassium channel activity
- Gene Name
- KCNK2
- Uniprot ID
- O95069
- Uniprot Name
- Potassium channel subfamily K member 2
- Molecular Weight
- 47092.215 Da
References
- Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
- Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [Article]
- Roukoz H, Saliba W: Dofetilide: a new class III antiarrhythmic agent. Expert Rev Cardiovasc Ther. 2007 Jan;5(1):9-19. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Inward rectifying potassium channel that is activated by phosphatidylinositol 4,5-bisphosphate and that probably participates in controlling the resting membrane potential in electrically excitable cells. Probably participates in establishing action potential waveform and excitability of neuronal and muscle tissues. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium
- Specific Function
- inward rectifier potassium channel activity
- Gene Name
- KCNJ12
- Uniprot ID
- Q14500
- Uniprot Name
- ATP-sensitive inward rectifier potassium channel 12
- Molecular Weight
- 49000.6 Da
References
- Kiehn J, Wible B, Lacerda AE, Brown AM: Mapping the block of a cloned human inward rectifier potassium channel by dofetilide. Mol Pharmacol. 1996 Aug;50(2):380-7. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
- Specific Function
- 1,8-cineole 2-exo-monooxygenase activity
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Walker DK, Alabaster CT, Congrave GS, Hargreaves MB, Hyland R, Jones BC, Reed LJ, Smith DA: Significance of metabolism in the disposition and action of the antidysrhythmic drug, dofetilide. In vitro studies and correlation with in vivo data. Drug Metab Dispos. 1996 Apr;24(4):447-55. [Article]
- Yamreudeewong W, DeBisschop M, Martin LG, Lower DL: Potentially significant drug interactions of class III antiarrhythmic drugs. Drug Saf. 2003;26(6):421-38. doi: 10.2165/00002018-200326060-00004. [Article]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Electrogenic voltage-dependent transporter that mediates the transport of a variety of organic cations such as endogenous bioactive amines, cationic drugs and xenobiotics (PubMed:9260930, PubMed:9687576). Functions as a Na(+)-independent, bidirectional uniporter (PubMed:21128598, PubMed:9687576). Cation cellular uptake or release is driven by the electrochemical potential, i.e. membrane potential and concentration gradient (PubMed:15212162, PubMed:9260930, PubMed:9687576). However, may also engage electroneutral cation exchange when saturating concentrations of cation substrates are reached (By similarity). Predominantly expressed at the basolateral membrane of hepatocytes and proximal tubules and involved in the uptake and disposition of cationic compounds by hepatic and renal clearance from the blood flow (PubMed:15783073). Implicated in monoamine neurotransmitters uptake such as histamine, dopamine, adrenaline/epinephrine, noradrenaline/norepinephrine, serotonin and tyramine, thereby supporting a physiological role in the central nervous system by regulating interstitial concentrations of neurotransmitters (PubMed:16581093, PubMed:17460754, PubMed:9687576). Also capable of transporting dopaminergic neuromodulators cyclo(his-pro), salsolinol and N-methyl-salsolinol, thereby involved in the maintenance of dopaminergic cell integrity in the central nervous system (PubMed:17460754). Mediates the bidirectional transport of acetylcholine (ACh) at the apical membrane of ciliated cell in airway epithelium, thereby playing a role in luminal release of ACh from bronchial epithelium (PubMed:15817714). Also transports guanidine and endogenous monoamines such as vitamin B1/thiamine, creatinine and N-1-methylnicotinamide (NMN) (PubMed:12089365, PubMed:15212162, PubMed:17072098, PubMed:24961373, PubMed:9260930). Mediates the uptake and efflux of quaternary ammonium compound choline (PubMed:9260930). Mediates the bidirectional transport of polyamine agmatine and the uptake of polyamines putrescine and spermidine (PubMed:12538837, PubMed:21128598). Able to transport non-amine endogenous compounds such as prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) (PubMed:11907186). Also involved in the uptake of xenobiotic 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP) (PubMed:12395288, PubMed:16394027). May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable)
- Specific Function
- acetylcholine transmembrane transporter activity
- Gene Name
- SLC22A2
- Uniprot ID
- O15244
- Uniprot Name
- Solute carrier family 22 member 2
- Molecular Weight
- 62579.99 Da
References
- Safety Data Sheet, Netupitant [Link]
Drug created at June 13, 2005 13:24 / Updated at August 02, 2024 07:23