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Identification
- Summary
Valbenazine is a vesicular monoamine transporter 2 inhibitor used to treat tardive dyskinesia and chorea associated with Huntington's disease.
- Brand Names
- Ingrezza
- Generic Name
- Valbenazine
- DrugBank Accession Number
- DB11915
- Background
Valbenazine is a modified metabolite of tetrabenazine, and it is currently being approved for the treatment of various movement disorders, particularly tardive dyskinesia and chorea associated with Huntington's disease.7,4 Tardive dyskinesia has long been regarded as a consequence of anti-dopamine receptor therapy, and until 2008 with the advent of tetrabenazine, most treatments were ineffective.5 However, challenges in using tetrabenazine as a treatment of tardive dyskinesia included frequent dosing and safety and tolerability concerns.5
On April 2017, valbenazine was approved by the FDA under the brand name INGREZZA as the first and only approved treatment for adults with Tardive Dyskinesia (TD).3 On August 2023, valbenazine was again approved by the FDA for the treatment of chorea associated with Huntington's disease respectively. This approval was supported by positive results in multiple trials, including the KINECT-HD Phase 3 study and the ongoing KINECT-HD2 open-label extension trial. The reduction in chorea severity was observed as early as 2 weeks after starting treatment with an initial dose of 40 mg.8
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Valbenazine (DB11915)
- Weight
- Average: 418.578
Monoisotopic: 418.283157712 - Chemical Formula
- C24H38N2O4
- Synonyms
- Valbenazine
- External IDs
- MT-5199
- NBI-98854
Pharmacology
- Indication
Valbenazine is indicated for the treatment of adults with tardive dyskinesia and chorea associated with Huntington’s disease.7
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Management of Chorea •••••••••••• ••••• ••••••• Management of Tardive dyskinesia •••••••••••• ••••• ••••••• - Contraindications & Blackbox Warnings
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Valbenazine inhibits human VMAT2 (Ki ~ 150 nM) with no appreciable binding affinity for VMAT1 (Ki > 10 µM). Valbenazine is converted to the active metabolite [+]-α-dihydrotetrabenazine ([+]-α-HTBZ). [+]-α-HTBZ also binds with relatively high affinity to human VMAT2 (Ki ~ 3 nM). Valbenazine and [+]-αHTBZ have no appreciable binding affinity (Ki > 5000 nM) for dopaminergic (including D2), serotonergic (including 5HT2B), adrenergic, histaminergic or muscarinic receptors, thus limiting off-target receptors binding for a more favorable safety profile.7,2,1
Valbenazine may cause an increase in the corrected QT interval in patients who are CYP2D6-poor metabolizers or who are taking a strong CYP2D6 or CYP3A4 inhibitor. An exposure-response analysis of clinical data from two healthy volunteer studies revealed increased QTc interval with higher plasma concentrations of the active metabolite. Based on this model, patients taking an valbenazine 60 mg or 80 mg dose with increased exposure to the metabolite (e.g., being a CYP2D6 poor metabolizer) may have a mean (upper bound of double-sided 90% CI) QT prolongation of 9.6 (12.0) msec or 11.7 (14.7) msec, respectively as compared to otherwise healthy volunteers given valbenazine, who had a respective mean (upper bound of double-sided 90% CI) QT prolongation of 5.3 (6.7) msec or 6.7 (8.4) msec.7
- Mechanism of action
Although the exact mechanism of action of valbenzine is still unknown, it is thought be mediated through the reversible inhibition of vesicular monoamine transporter 2 (VMAT2), a transporter that regulates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release.7
Target Actions Organism ASynaptic vesicular amine transporter inhibitorHumans - Absorption
Valbenazine and its active metabolite ([+]-α-HTBZ) demonstrate approximate proportional increases for the area under the plasma concentration versus time curve (AUC) and maximum plasma concentration (Cmax) after single oral doses from 40 mg to 300 mg (i.e., 50% to 375% of the recommended treatment dose).7
Following oral administration, the time to reach maximum valbenazine plasma concentration (Tmax) ranges from 0.5 to 1.0 hours. Valbenazine reaches steady-state plasma concentrations within 1 week. The absolute oral bioavailability of valbenazine is approximately 49%. [+]-α-HTBZ gradually forms and reaches Cmax 4 to 8 hours after administration of valbenazine.7
Ingestion of a high-fat meal decreases valbenazine Cmax by approximately 47% and AUC by approximately 13%. [+]-α-HTBZ Cmax and AUC are unaffected.7
- Volume of distribution
The mean steady-state volume of distribution of valbenazine is 92 L.7
- Protein binding
The plasma protein binding of valbenazine and [+]-α-HTBZ is greater than 99% and approximately 64%, respectively.7
- Metabolism
Valbenazine is extensively metabolized after oral administration by hydrolysis of the valine ester to form the active metabolite ([+]-α-HTBZ) and by oxidative metabolism, primarily by CYP3A4/5, to form mono-oxidized valbenazine and other minor metabolites. [+]-α-HTBZ appears to be further metabolized in part by CYP2D6.7
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- Route of elimination
Following the administration of a single 50-mg oral dose of radiolabeled C-valbenazine (i.e., ~63% of the recommended treatment dose), approximately 60% and 30% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 2% was excreted as unchanged valbenazine or [+]-α-HTBZ in either urine or feces.7
- Half-life
Both Valbenazine and [+]-α-HTBZ have half-lives of 15 to 22 hours.7
- Clearance
Valbenazine has a mean total plasma systemic clearance value of 7.2 L/hr.7
- Adverse Effects
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The limited available data on valbenazine use in pregnant women are insufficient to inform a drug-associated risk. In animal reproductive studies, no malformations were observed when valbenazine was administered orally to rats and rabbits during the period of organogenesis at doses up to 1.8 or 24 times, respectively, the maximum recommended human dose (MRHD) of 80 mg/day based on mg/m2 body surface area. However, administration of valbenazine to pregnant rats during organogenesis through lactation produced an increase in the number of stillborn pups and postnatal pup mortalities at doses <1 times the MRHD based on mg/m2. Advise a pregnant woman of the potential risk to a fetus.7
In a fertility study, rats were treated orally with valbenazine at 1, 3, and 10 mg/kg/day prior to mating and through mating, for a minimum of 10 weeks (males) or through Day 7 of gestation (females). These doses are 0.1, 0.4, and 1.2 times the MRHD of 80 mg/day based on mg/m2, respectively. Valbenazine delayed mating in both sexes, which led to a lower number of pregnancies and disrupted estrous cyclicity at the high dose, 1.2 times the MRHD of 80 mg/day based on mg/m2. Valbenazine had no effects on sperm parameters (motility, count, density) or on uterine parameters (corpora lutea, number of implants, viable implants, pre-implantation loss, early resorptions, and post-implantation loss) at any dose.7
Patients with moderate to severe hepatic impairment (Child-Pugh score 7 to 15) had higher exposure of valbenazine and its active metabolite than patients with normal hepatic function.7
Valbenazine did not increase tumors in rats treated orally for 91 weeks at 0.5, 1, and 2 mg/kg/day. These doses are <1 times (0.06, 0.1, and 0.24 times, respectively) the MRHD of 80 mg/day based on mg/m2.7
Valbenazine did not increase tumors in hemizygous Tg.rasH2 mice treated orally for 26 weeks at 10, 30, and 75 mg/kg/day, which are 0.6, 1.9, and 4.6 times the MRHD of 80 mg/day based on mg/m2.7
Valbenazine was not mutagenic in the in vitro bacterial reverse mutation test (Ames) or clastogenic in the in vitro mammalian chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo rat bone marrow micronucleus assay.7
No specific antidotes for valbenazine are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. If an overdose occurs, consult a Certified Poison Control Center.7
- 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 softwareAbacavir Abacavir may decrease the excretion rate of Valbenazine which could result in a higher serum level. Abametapir The serum concentration of Valbenazine can be increased when it is combined with Abametapir. Abatacept The metabolism of Valbenazine can be increased when combined with Abatacept. Abiraterone The metabolism of Valbenazine can be decreased when combined with Abiraterone. Acalabrutinib The metabolism of Valbenazine can be decreased when combined with Acalabrutinib. - Food Interactions
- Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of valbenazine.
- 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 Ingredients
Ingredient UNII CAS InChI Key Valbenazine tosylate 5SML1T733B 1639208-54-0 BXGKAGLZHGYAMW-TZYFFPFWSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Ingrezza Capsule 60 mg/1 Oral Neurocrine Biosciences, Inc. 2021-04-23 Not applicable US 
Ingrezza Capsule 80 mg/1 Oral Neurocrine Biosciences, Inc. 2017-10-04 Not applicable US Ingrezza Capsule 40 mg/1 Oral Neurocrine Biosciences, Inc. 2017-04-20 2021-02-25 US Ingrezza Capsule 40 mg/1 Oral Neurocrine Biosciences, Inc. 2018-12-14 Not applicable US INGREZZA Sprinkle Capsule 80 mg/1 Oral Neurocrine Biosciences, Inc. 2024-04-30 Not applicable US - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Ingrezza Valbenazine (40 mg/1) + Valbenazine (80 mg/1) Kit Oral Neurocrine Biosciences, Inc. 2018-08-14 2020-03-07 US Ingrezza Valbenazine tosylate (40 mg/1) + Valbenazine tosylate (80 mg/1) Kit Oral Neurocrine Biosciences, Inc. 2018-12-14 Not applicable US Ingrezza Valbenazine (40 mg/1) + Valbenazine (80 mg/1) Kit Oral Neurocrine Biosciences, Inc. 2018-08-14 2020-03-07 US Ingrezza Valbenazine tosylate (40 mg/1) + Valbenazine tosylate (60 mg/1) Kit Oral Neurocrine Biosciences, Inc. 2023-08-18 Not applicable US Ingrezza Valbenazine tosylate (40 mg/1) + Valbenazine tosylate (80 mg/1) Kit Oral Neurocrine Biosciences, Inc. 2018-12-14 Not applicable US
Categories
- ATC Codes
- N07XX13 — Valbenazine
- Drug Categories
- Amino Acids
- Amino Acids, Branched-Chain
- Amino Acids, Peptides, and Proteins
- Cytochrome P-450 CYP2D6 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A5 Substrates
- Cytochrome P-450 Substrates
- Drugs that are Mainly Renally Excreted
- Heterocyclic Compounds, Fused-Ring
- Nervous System
- Quinolizines
- Vesicular Monoamine Transporter 2 Inhibitor
- Vesicular Monoamine Transporter 2 Inhibitors
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as alpha amino acid esters. These are ester derivatives of alpha amino acids.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Carboxylic acids and derivatives
- Sub Class
- Amino acids, peptides, and analogues
- Direct Parent
- Alpha amino acid esters
- Alternative Parents
- Valine and derivatives / Tetrahydroisoquinolines / Anisoles / Fatty acid esters / Aralkylamines / Alkyl aryl ethers / Piperidines / Trialkylamines / Carboxylic acid esters / Monocarboxylic acids and derivatives show 5 more
- Substituents
- Alkyl aryl ether / Alpha-amino acid ester / Amine / Anisole / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Carbonyl group / Carboxylic acid ester show 19 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 54K37P50KH
- CAS number
- 1025504-45-3
- InChI Key
- GEJDGVNQKABXKG-CFKGEZKQSA-N
- InChI
- InChI=1S/C24H38N2O4/c1-14(2)9-17-13-26-8-7-16-10-21(28-5)22(29-6)11-18(16)19(26)12-20(17)30-24(27)23(25)15(3)4/h10-11,14-15,17,19-20,23H,7-9,12-13,25H2,1-6H3/t17-,19-,20-,23+/m1/s1
- IUPAC Name
- (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl (2S)-2-amino-3-methylbutanoate
- SMILES
- COC1=C(OC)C=C2[C@H]3C[C@@H](OC(=O)[C@@H](N)C(C)C)[C@H](CC(C)C)CN3CCC2=C1
References
- General References
- O'Brien CF, Jimenez R, Hauser RA, Factor SA, Burke J, Mandri D, Castro-Gayol JC: NBI-98854, a selective monoamine transport inhibitor for the treatment of tardive dyskinesia: A randomized, double-blind, placebo-controlled study. Mov Disord. 2015 Oct;30(12):1681-7. doi: 10.1002/mds.26330. Epub 2015 Sep 8. [Article]
- Grigoriadis DE, Smith E, Hoare SRJ, Madan A, Bozigian H: Pharmacologic Characterization of Valbenazine (NBI-98854) and Its Metabolites. J Pharmacol Exp Ther. 2017 Jun;361(3):454-461. doi: 10.1124/jpet.116.239160. Epub 2017 Apr 12. [Article]
- Witek N, Comella C: Valbenazine in the treatment of tardive dyskinesia. Neurodegener Dis Manag. 2019 Apr;9(2):73-81. doi: 10.2217/nmt-2019-0001. Epub 2019 Feb 6. [Article]
- Harriott ND, Williams JP, Smith EB, Bozigian HP, Grigoriadis DE: VMAT2 Inhibitors and the Path to Ingrezza (Valbenazine). Prog Med Chem. 2018;57(1):87-111. doi: 10.1016/bs.pmch.2017.12.002. Epub 2018 Mar 7. [Article]
- Citrome L: Valbenazine for tardive dyskinesia: A systematic review of the efficacy and safety profile for this newly approved novel medication-What is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract. 2017 Jul;71(7). doi: 10.1111/ijcp.12964. Epub 2017 May 12. [Article]
- FDA Approved Drug Products: Ingrezza (valbenazine) oral capsules [Link]
- FDA Approved Drug Products: INGREZZA® (valbenazine) capsules, for oral use (August 2023) [Link]
- Neurocrine Biosciences Announces FDA Approval of INGREZZA® (valbenazine) Capsules for the Treatment of Chorea Associated With Huntington's Disease [Link]
- External Links
- PubChem Compound
- 24795069
- PubChem Substance
- 347828246
- ChemSpider
- 28536134
- 1918219
- ChEMBL
- CHEMBL2364639
- ZINC
- ZINC000043195697
- Wikipedia
- Valbenazine
- FDA label
- Download (358 KB)
- MSDS
- Download (21.3 KB)
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 data4 Active Not Recruiting Treatment Bipolar Disorder (BD) / Major Depressive Disorder (MDD) / Schizoaffective Disorders / Schizophrenia / Tardive Dyskinesia (TD) 1 somestatus stop reason just information to hide 4 Completed Treatment Cervical Dystonia 1 somestatus stop reason just information to hide 4 Completed Treatment Tardive Dyskinesia (TD) 2 somestatus stop reason just information to hide 4 Not Yet Recruiting Treatment Disability, Developmental / Intellectual Disabilities / Tardive Dyskinesia (TD) 1 somestatus stop reason just information to hide 3 Active Not Recruiting Treatment Huntington's Disease (HD) 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 40 mg/1 Capsule Oral 60 mg/1 Capsule Oral 80 mg/1 Kit Oral Capsule Oral 73 MG Capsule, gelatin coated Oral 40 mg Capsule Oral 40 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8039627 No 2011-10-18 2029-10-06 US US8357697 No 2013-01-22 2027-11-08 US US10065952 No 2018-09-04 2036-10-28 US US10874648 No 2020-12-29 2037-10-10 US US10857137 No 2020-12-08 2037-10-10 US US10857148 No 2020-12-08 2037-10-10 US US10844058 No 2020-11-24 2036-10-28 US US10851103 No 2020-12-01 2036-10-28 US US10851104 No 2020-12-01 2036-10-28 US US10912771 No 2021-02-09 2037-10-10 US US10919892 No 2021-02-16 2036-12-22 US US10906902 No 2021-02-02 2036-12-22 US US10906903 No 2021-02-02 2036-12-22 US US10952997 No 2021-03-23 2037-10-10 US US10940141 No 2021-03-09 2040-08-10 US US10993941 No 2021-05-04 2037-10-10 US US11026931 No 2021-06-08 2039-08-14 US US11026939 No 2021-06-08 2038-09-18 US US11040029 No 2021-06-22 2037-10-10 US US11311532 No 2018-09-18 2038-09-18 US US11654142 No 2018-11-14 2038-11-14 US US11439629 No 2017-10-10 2037-10-10 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0383 mg/mL ALOGPS logP 3.63 ALOGPS logP 3.65 Chemaxon logS -4 ALOGPS pKa (Strongest Basic) 8.41 Chemaxon Physiological Charge 2 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 74.02 Å2 Chemaxon Rotatable Bond Count 8 Chemaxon Refractivity 118.4 m3·mol-1 Chemaxon Polarizability 48.97 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-014i-0000900000-1cadb118dacf8b8fb373 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-014i-0200900000-514a8356e2c8171d1af4 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0uxr-2009700000-d2cde83a552882a3aa52 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-014j-9603100000-ab588e1c17ed1098794f Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0pvl-3179300000-fcbd9204216572e6668b Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-029l-0059100000-2c655f78d0a076010bde Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 202.79527 predictedDeepCCS 1.0 (2019) [M+H]+ 205.19086 predictedDeepCCS 1.0 (2019) [M+Na]+ 211.10338 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Electrogenic antiporter that exchanges one cationic monoamine with two intravesicular protons across the membrane of secretory and synaptic vesicles. Uses the electrochemical proton gradient established by the V-type proton-pump ATPase to accumulate high concentrations of monoamines inside the vesicles prior to their release via exocytosis. Transports a variety of catecholamines such as dopamine, adrenaline and noradrenaline, histamine, and indolamines such as serotonin (PubMed:23363473, PubMed:8643547). Regulates the transvesicular monoaminergic gradient that determines the quantal size. Mediates somatodendritic dopamine release in hippocampal neurons, likely as part of a regulated secretory pathway that integrates retrograde synaptic signals (By similarity). Acts as a primary transporter for striatal dopamine loading ensuring impulse-dependent release of dopamine at the synaptic cleft (By similarity). Responsible for histamine and serotonin storage and subsequent corelease from mast cell granules (By similarity) (PubMed:8860238)
- Specific Function
- Monoamine transmembrane transporter activity
- Gene Name
- SLC18A2
- Uniprot ID
- Q05940
- Uniprot Name
- Synaptic vesicular amine transporter
- Molecular Weight
- 55712.075 Da
References
- FDA Approved Drug Products: INGREZZA® (valbenazine) capsules, for oral use (August 2023) [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, 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) (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:19965576, PubMed:20972997). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:18698000, PubMed:21289075). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid (PubMed:10681376). Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants
- Specific Function
- Anandamide 11,12 epoxidase activity
- Gene Name
- CYP2D6
- Uniprot ID
- P10635
- Uniprot Name
- Cytochrome P450 2D6
- Molecular Weight
- 55768.94 Da
References
- FDA Approved Drug Products: INGREZZA® (valbenazine) capsules, for oral use (August 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- 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
- FDA Approved Drug Products: INGREZZA® (valbenazine) capsules, for oral use (August 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and vitamins (PubMed:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). 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:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). Exhibits high catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes 6beta-hydroxylation of the steroid hormones testosterone, progesterone, and androstenedione (PubMed:2732228). Catalyzes the oxidative conversion 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 all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Also involved in the oxidative metabolism of xenobiotics, including calcium channel blocking drug nifedipine and immunosuppressive drug cyclosporine (PubMed:2732228)
- Specific Function
- Aromatase activity
- Gene Name
- CYP3A5
- Uniprot ID
- P20815
- Uniprot Name
- Cytochrome P450 3A5
- Molecular Weight
- 57108.065 Da
References
- FDA Approved Drug Products: INGREZZA® (valbenazine) capsules, for oral use (August 2023) [Link]
Drug created at October 20, 2016 21:00 / Updated at February 13, 2024 02:57