Levomilnacipran
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Identification
- Summary
Levomilnacipran is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) used to treat major depressive disorder (MDD) in adults.
- Brand Names
- Fetzima
- Generic Name
- Levomilnacipran
- DrugBank Accession Number
- DB08918
- Background
Levomilnacipran is a selective serotonin and norepinephrine reuptake inhibitor (SNRI), although it is a more potent inhibitor of norepinephrine reuptake than serotonin reuptake.2,3 Levomilnacipran is the more active 1S,2R-enantiomer in the racemate milnacipran.2,6 Once administered, interconversion between levomilnacipran and its stereoisomer does not occur in humans.4 First approved by the FDA on July 25, 2013, levomilnacipran is used to treat major depressive disorder in adults.6 While levomilnacipran was previously investigated and proposed as a potential treatment for stroke in Europe, the EMA decided against this use.7
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 246.348
Monoisotopic: 246.173213336 - Chemical Formula
- C15H22N2O
- Synonyms
- (1S,2R)-milnacipran
- CYCLOPROPANECARBOXAMIDE, 2-(AMINOMETHYL)-N,N-DIETHYL-1-PHENYL-, (1S,2R)-
- Levomilnacipran
- MILNACIPRAN, (1S,2R)-
- External IDs
- F 2695
- F-2695
- F2695
Pharmacology
- Indication
Levomilnacipran is a serotonin and norepinephrine reuptake inhibitor indicated for the treatment of major depressive disorder (MDD) in adults.4
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Management of Major depressive disorder •••••••••••• ••••• - Contraindications & Blackbox Warnings
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- Pharmacodynamics
Levomilnacipran is an antidepressant that binds with high affinity to human serotonin (5-HT) and norepinephrine (NE) transporters (Ki = 11 and 91 nM, respectively). It potently inhibits 5-HT and NE reuptake (IC50 = 16 - 19 and 11 nM, respectively).4 Levomilnacipran does not bind to any other receptors, ion channels, or transporters, including serotonergic (5HT1-7), α- and β adrenergic, muscarinic, or histaminergic receptors and Ca2+, Na+, K+ or Cl- channels to a significant degree.1,3,4 Levomilnacipran did not inhibit monoamine oxidase (MAO). Furthermore, levomilnacipran does not prolong the QTc interval to a clinically relevant extent.4
- Mechanism of action
Levomilnacipran is a potent and selective selective serotonin and norepinephrine reuptake inhibitor (SNRI). The exact mechanism of the antidepressant action of levomilnacipran is unknown but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system through inhibition of reuptake at serotonin and norepinephrine transporters.4 Like milnacipran, levomilnacipran is a more potent inhibitor of the norepinephrine transporter than the serotonin transporter:3 it exhibits over a 15-fold higher selectivity for norepinephrine versus serotonin reuptake inhibition.1
Target Actions Organism ASodium-dependent serotonin transporter inhibitorHumans ASodium-dependent noradrenaline transporter inhibitorHumans - Absorption
The steady-state concentration of levomilnacipran was dose-proportional when administered at a dose ranging from 25 mg to 300 mg (2.5 times the maximum recommended dosage of levomilnacipran) once daily. After daily dosing of 120 mg levomilnacipran, the mean Cmax value was 341 ng/mL, and the mean steady-state AUC value was 5196 ng x h/mL.4
The relative bioavailability of oral levomilnacipran extended-release capsules was 92% when compared to oral solution. The median time to peak concentration (Tmax) of levomilnacipran ranges from six to eight hours after oral administration. Levomilnacipran concentration was not significantly affected when it was administered with food.4
- Volume of distribution
Levomilnacipran is widely distributed, with an apparent volume of distribution ranging from 387 to 473 L.4
- Protein binding
Levomilnacipran is 22% bound to plasma proteins over the concentration range of 10 to 1000 ng/mL.4
- Metabolism
Levomilnacipran undergoes desethylation to form desethyl levomilnacipran (or N-desethyl levomilnacipran) and hydroxylation to form p-hydroxy-levomilnacipran, which are pharmacologically inactive. Both oxidative metabolites can undergo further glucuronidation. Desethylation is primarily catalyzed by CYP3A4 with minor contributions by CYP2C8, 2C19, 2D6, and 2J2.3,4
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- Route of elimination
Levomilnacipran and its metabolites are eliminated primarily by renal excretion. Following oral administration of 14C-levomilnacipran solution, approximately 58% of the dose is excreted in urine as unchanged levomilnacipran. N-desethyl levomilnacipran was the major metabolite excreted in the urine, accounting for approximately 18% of the dose. Other identifiable metabolites excreted in the urine were levomilnacipran glucuronide (4%), desethyl levomilnacipran glucuronide (3%), p-hydroxy levomilnacipran glucuronide (1%), and p-hydroxy levomilnacipran (1%).4
- Half-life
The apparent terminal elimination half-life of extended-release levomilnacipran is approximately 12 hours.4
- Clearance
Following oral administration, the mean apparent total clearance of levomilnacipran is 21-29 L/h.4
- 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
The oral LD50 in rats was 238 mg/kg.5
There is limited clinical experience with levomilnacipran overdose in humans. In clinical studies, cases of ingestions up to 360 mg daily were reported with none being fatal. As there is no known specific antidote, levomilnacipran overdose should be managed with supportive measures, including close medical supervision and monitoring, with the consideration of possible multiple drug involvement. The high volume of distribution of levomilnacipran suggests that dialysis will not be effective in reducing levomilnacipran plasma concentrations.4
- 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 Levomilnacipran which could result in a higher serum level. Abametapir The serum concentration of Levomilnacipran can be increased when it is combined with Abametapir. Abciximab The risk or severity of bleeding can be increased when Abciximab is combined with Levomilnacipran. Acarbose The risk or severity of hypoglycemia can be increased when Levomilnacipran is combined with Acarbose. Aceclofenac Levomilnacipran may increase the antiplatelet activities of Aceclofenac. - Food Interactions
- Avoid alcohol. Ingesting alcohol may compromise the extended-release dosage form of levomilnacipran, causing an accelerated release of the drug and increasing its serum concentration.
- Avoid herbs and supplements with anticoagulant/antiplatelet activity. Taking herbs with antiplatelet or anticoagulant activity may increase the risk of bleeding.
- Exercise caution with grapefruit products. Grapefruit is a moderate to strong CYP3A4 inhibitor. Do not exceed a maximum levomilnacipran dose of 80mg daily when taking strong CYP3A4 inhibitors.
- Exercise caution with St. John's Wort. Administering levomilnacipran with St. John's Wort may increase the risk of serotonin syndrome.
- Take with or without food. Food does not affect drug absorption and exposure to a clinically significant extent.
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 Levomilnacipran hydrochloride 371U2ZK31U 175131-60-9 XNCDYJFPRPDERF-NQQJLSKUSA-N - Product Images
- Brand Name Prescription Products
- Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Levomilnacipran Capsule, extended release 80 mg/1 Oral Amneal Pharmaceuticals LLC 2019-02-04 Not applicable US Levomilnacipran Capsule, extended release 40 mg/1 Oral Amneal Pharmaceuticals LLC 2019-02-04 Not applicable US Levomilnacipran Capsule, extended release 120 mg/1 Oral Amneal Pharmaceuticals LLC 2019-02-04 Not applicable US Levomilnacipran Capsule, extended release 20 mg/1 Oral Amneal Pharmaceuticals LLC 2019-02-04 Not applicable US - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Fetzima Levomilnacipran hydrochloride (20 mg/1) + Levomilnacipran hydrochloride (40 mg/1) Kit Oral Allergan, Inc. 2023-03-24 Not applicable US Fetzima Levomilnacipran hydrochloride (20 mg/1) + Levomilnacipran hydrochloride (40 mg/1) Kit Oral Allergan, Inc. 2013-07-25 Not applicable US Fetzima Levomilnacipran hydrochloride (20 mg/1) + Levomilnacipran hydrochloride (40 mg/1) Kit Oral Allergan, Inc. 2023-03-24 Not applicable US Fetzima Levomilnacipran hydrochloride (20 mg/1) + Levomilnacipran hydrochloride (40 mg/1) Kit Oral Allergan, Inc. 2013-07-25 Not applicable US
Categories
- ATC Codes
- N06AX28 — Levomilnacipran
- Drug Categories
- Adrenergic Uptake Inhibitors
- Agents producing tachycardia
- Antidepressive Agents
- Antidepressive Agents Indicated for Depression
- Central Nervous System Agents
- Central Nervous System Depressants
- Combined Inhibitors of Serotonin/Norepinephrine Reuptake
- Cycloparaffins
- Cyclopropanes
- Cytochrome P-450 CYP2C19 Substrates
- Cytochrome P-450 CYP2C8 Substrates
- Cytochrome P-450 CYP2D6 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- Drugs that are Mainly Renally Excreted
- Hypoglycemia-Associated Agents
- Membrane Transport Modulators
- Miscellaneous Antidepressants
- Nervous System
- Neurotransmitter Agents
- Neurotransmitter Uptake Inhibitors
- Norepinephrine Uptake Inhibitors
- P-glycoprotein substrates
- Psychoanaleptics
- Psychotropic Drugs
- Serotonergic Drugs Shown to Increase Risk of Serotonin Syndrome
- Serotonin Agents
- Serotonin and Noradrenaline Reuptake Inhibitors
- Serotonin Modulators
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as phenylacetamides. These are amide derivatives of phenylacetic acids.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Phenylacetamides
- Direct Parent
- Phenylacetamides
- Alternative Parents
- Aralkylamines / Cyclopropanecarboxylic acids and derivatives / Tertiary carboxylic acid amides / Amino acids and derivatives / Organopnictogen compounds / Organic oxides / Monoalkylamines / Hydrocarbon derivatives / Carbonyl compounds
- Substituents
- Amine / Amino acid or derivatives / Aralkylamine / Aromatic homomonocyclic compound / Carbonyl group / Carboxamide group / Carboxylic acid derivative / Cyclopropanecarboxylic acid or derivatives / Hydrocarbon derivative / Organic nitrogen compound
- Molecular Framework
- Aromatic homomonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- UGM0326TXX
- CAS number
- 96847-54-0
- InChI Key
- GJJFMKBJSRMPLA-DZGCQCFKSA-N
- InChI
- InChI=1S/C15H22N2O/c1-3-17(4-2)14(18)15(10-13(15)11-16)12-8-6-5-7-9-12/h5-9,13H,3-4,10-11,16H2,1-2H3/t13-,15+/m0/s1
- IUPAC Name
- (1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropane-1-carboxamide
- SMILES
- CCN(CC)C(=O)[C@]1(C[C@H]1CN)C1=CC=CC=C1
References
- General References
- Asnis GM, Henderson MA: Levomilnacipran for the treatment of major depressive disorder: a review. Neuropsychiatr Dis Treat. 2015 Jan 9;11:125-35. doi: 10.2147/NDT.S54710. eCollection 2015. [Article]
- Mago R, Mahajan R, Thase ME: Levomilnacipran: a newly approved drug for treatment of major depressive disorder. Expert Rev Clin Pharmacol. 2014 Mar;7(2):137-45. doi: 10.1586/17512433.2014.889563. [Article]
- Bruno A, Morabito P, Spina E, Muscatello MR: The Role of Levomilnacipran in the Management of Major Depressive Disorder: A Comprehensive Review. Curr Neuropharmacol. 2016;14(2):191-9. [Article]
- FDA Approved Drug Products: FETZIMA (levomilnacipran) extended-release capsules, for oral use (August 2023) [Link]
- Allergan: FETZIMA (Levomilnacipran) MSDS [Link]
- FDA Drug Approval Package: FETZIMA (levomilnacipran) Extended-Release Capsules [Link]
- European Medicines Agency decision: P/0128/2015 [Link]
- External Links
- KEGG Drug
- D10072
- PubChem Compound
- 6917779
- PubChem Substance
- 175427154
- ChemSpider
- 5293005
- BindingDB
- 50032379
- 1433212
- ChEBI
- 136040
- ChEMBL
- CHEMBL99946
- ZINC
- ZINC000000000506
- Wikipedia
- Levomilnacipran
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 Other Tobacco Use Disorders 1 somestatus stop reason just information to hide 4 Completed Treatment Major Depressive Disorder (MDD) 3 somestatus stop reason just information to hide 4 Unknown Status Basic Science None (i.e. Healthy Volunteers) 1 somestatus stop reason just information to hide 3 Completed Treatment Depression / Major Depressive Disorder (MDD) 1 somestatus stop reason just information to hide 3 Completed Treatment Ischemic Stroke 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 20.000 mg Capsule, extended release Oral 120 mg Capsule, extended release Oral 20 mg Capsule, extended release Oral 40 mg Capsule, extended release Oral 80 mg Kit Oral Capsule, extended release Oral 120 mg/1 Capsule, extended release Oral 20 mg/1 Capsule, extended release Oral 40 mg/1 Capsule, extended release Oral 80 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region USRE43879 No 2012-12-25 2023-06-03 US US8481598 No 2013-07-09 2031-03-02 US US8865937 No 2014-10-21 2032-05-23 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 1.23 mg/mL ALOGPS logP 1.72 ALOGPS logP 1.42 Chemaxon logS -2.3 ALOGPS pKa (Strongest Basic) 9.83 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 2 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 46.33 Å2 Chemaxon Rotatable Bond Count 5 Chemaxon Refractivity 73.81 m3·mol-1 Chemaxon Polarizability 28.34 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 + 1.0 Blood Brain Barrier + 0.9889 Caco-2 permeable + 0.5914 P-glycoprotein substrate Substrate 0.5928 P-glycoprotein inhibitor I Non-inhibitor 0.902 P-glycoprotein inhibitor II Non-inhibitor 0.8787 Renal organic cation transporter Non-inhibitor 0.8119 CYP450 2C9 substrate Non-substrate 0.8494 CYP450 2D6 substrate Non-substrate 0.9116 CYP450 3A4 substrate Non-substrate 0.6514 CYP450 1A2 substrate Non-inhibitor 0.6383 CYP450 2C9 inhibitor Non-inhibitor 0.7697 CYP450 2D6 inhibitor Non-inhibitor 0.7718 CYP450 2C19 inhibitor Non-inhibitor 0.8587 CYP450 3A4 inhibitor Non-inhibitor 0.6327 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.7004 Ames test Non AMES toxic 0.8013 Carcinogenicity Non-carcinogens 0.5456 Biodegradation Not ready biodegradable 0.9972 Rat acute toxicity 2.6162 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.993 hERG inhibition (predictor II) Non-inhibitor 0.6823
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS splash10-0002-5910000000-6041b8fa3fe52b885b2c Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0002-0690000000-e358699dd4ba3ced536b Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-000t-3970000000-6a00667afb142f57e896 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0002-3390000000-4a22ea8684355b17c232 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-00kb-9360000000-32dc0f23bf29a8d2ba83 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-00fr-9300000000-77df58f97fce227ecf77 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-014i-9700000000-217adea06b61e02741c0 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]- 157.74638 predictedDeepCCS 1.0 (2019) [M+H]+ 160.10439 predictedDeepCCS 1.0 (2019) [M+Na]+ 166.19753 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- Curator comments
- Levomilnacipran inhibits the human serotonin transporter with an inhibitory constant (Ki) of 11 nM.
- General Function
- Serotonin transporter that cotransports serotonin with one Na(+) ion in exchange for one K(+) ion and possibly one proton in an overall electroneutral transport cycle. Transports serotonin across the plasma membrane from the extracellular compartment to the cytosol thus limiting serotonin intercellular signaling (PubMed:10407194, PubMed:12869649, PubMed:21730057, PubMed:27049939, PubMed:27756841, PubMed:34851672). Essential for serotonin homeostasis in the central nervous system. In the developing somatosensory cortex, acts in glutamatergic neurons to control serotonin uptake and its trophic functions accounting for proper spatial organization of cortical neurons and elaboration of sensory circuits. In the mature cortex, acts primarily in brainstem raphe neurons to mediate serotonin uptake from the synaptic cleft back into the pre-synaptic terminal thus terminating serotonin signaling at the synapse (By similarity). Modulates mucosal serotonin levels in the gastrointestinal tract through uptake and clearance of serotonin in enterocytes. Required for enteric neurogenesis and gastrointestinal reflexes (By similarity). Regulates blood serotonin levels by ensuring rapid high affinity uptake of serotonin from plasma to platelets, where it is further stored in dense granules via vesicular monoamine transporters and then released upon stimulation (PubMed:17506858, PubMed:18317590). Mechanistically, the transport cycle starts with an outward-open conformation having Na1(+) and Cl(-) sites occupied. The binding of a second extracellular Na2(+) ion and serotonin substrate leads to structural changes to outward-occluded to inward-occluded to inward-open, where the Na2(+) ion and serotonin are released into the cytosol. Binding of intracellular K(+) ion induces conformational transitions to inward-occluded to outward-open and completes the cycle by releasing K(+) possibly together with a proton bound to Asp-98 into the extracellular compartment. Na1(+) and Cl(-) ions remain bound throughout the transport cycle (PubMed:10407194, PubMed:12869649, PubMed:21730057, PubMed:27049939, PubMed:27756841, PubMed:34851672). Additionally, displays serotonin-induced channel-like conductance for monovalent cations, mainly Na(+) ions. The channel activity is uncoupled from the transport cycle and may contribute to the membrane resting potential or excitability (By similarity)
- Specific Function
- actin filament binding
- Gene Name
- SLC6A4
- Uniprot ID
- P31645
- Uniprot Name
- Sodium-dependent serotonin transporter
- Molecular Weight
- 70324.165 Da
References
- FDA Approved Drug Products: FETZIMA (levomilnacipran) extended-release capsules, for oral use (August 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- Curator comments
- Levomilnacipran inhibits the human norepinephrine transporter with an inhibitory constant (Ki) of 91 nM.
- General Function
- Mediates sodium- and chloride-dependent transport of norepinephrine (also known as noradrenaline) (PubMed:2008212, PubMed:8125921). Can also mediate sodium- and chloride-dependent transport of dopamine (PubMed:11093780, PubMed:8125921)
- Specific Function
- actin binding
- Gene Name
- SLC6A2
- Uniprot ID
- P23975
- Uniprot Name
- Sodium-dependent noradrenaline transporter
- Molecular Weight
- 69331.42 Da
References
- FDA Approved Drug Products: FETZIMA (levomilnacipran) extended-release capsules, for oral use (August 2023) [Link]
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
- FDA Approved Drug Products: FETZIMA (levomilnacipran) extended-release capsules, for oral use (August 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). 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:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:15766564, PubMed:19965576, PubMed:7574697). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316)
- Specific Function
- arachidonic acid epoxygenase activity
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- Bruno A, Morabito P, Spina E, Muscatello MR: The Role of Levomilnacipran in the Management of Major Depressive Disorder: A Comprehensive Review. Curr Neuropharmacol. 2016;14(2):191-9. [Article]
- FDA Approved Drug Products: FETZIMA (levomilnacipran) extended-release capsules, for oral use (August 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) (PubMed:18577768, PubMed:19965576, PubMed:20972997). 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:18577768, PubMed:19965576, PubMed:20972997). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates PUFA specifically at the omega-1 position (PubMed:18577768). Catalyzes the epoxidation of double bonds of PUFA (PubMed:19965576, PubMed:20972997). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Hydroxylates fenbendazole at the 4' position (PubMed:23959307)
- Specific Function
- (R)-limonene 6-monooxygenase activity
- Gene Name
- CYP2C19
- Uniprot ID
- P33261
- Uniprot Name
- Cytochrome P450 2C19
- Molecular Weight
- 55944.565 Da
References
- Bruno A, Morabito P, Spina E, Muscatello MR: The Role of Levomilnacipran in the Management of Major Depressive Disorder: A Comprehensive Review. Curr Neuropharmacol. 2016;14(2):191-9. [Article]
- FDA Approved Drug Products: FETZIMA (levomilnacipran) extended-release capsules, for oral use (August 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- 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
- Bruno A, Morabito P, Spina E, Muscatello MR: The Role of Levomilnacipran in the Management of Major Depressive Disorder: A Comprehensive Review. Curr Neuropharmacol. 2016;14(2):191-9. [Article]
- FDA Approved Drug Products: FETZIMA (levomilnacipran) extended-release capsules, for oral use (August 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) in the cardiovascular system (PubMed:19965576, PubMed:8631948). 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:19965576, PubMed:8631948). Catalyzes the epoxidation of double bonds of PUFA (PubMed:19965576, PubMed:8631948). Converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EpETrE), likely playing a major role in the epoxidation of endogenous cardiac arachidonic acid pools (PubMed:8631948). In endothelial cells, participates in eicosanoids metabolism by converting hydroperoxide species into hydroxy epoxy metabolites. In combination with 15-lipoxygenase metabolizes arachidonic acid and converts hydroperoxyicosatetraenoates (HpETEs) into hydroxy epoxy eicosatrienoates (HEETs), which are precursors of vasodilatory trihydroxyicosatrienoic acids (THETAs). This hydroperoxide isomerase activity is NADPH- and O2-independent (PubMed:19737933). Catalyzes the monooxygenation of a various xenobiotics, such as danazol, amiodarone, terfenadine, astemizole, thioridazine, tamoxifen, cyclosporin A and nabumetone (PubMed:19923256). Catalyzes hydroxylation of the anthelmintics albendazole and fenbendazole (PubMed:23959307). Catalyzes the sulfoxidation of fenbedazole (PubMed:19923256)
- Specific Function
- arachidonic acid 11,12-epoxygenase activity
- Gene Name
- CYP2J2
- Uniprot ID
- P51589
- Uniprot Name
- Cytochrome P450 2J2
- Molecular Weight
- 57610.165 Da
References
- Bruno A, Morabito P, Spina E, Muscatello MR: The Role of Levomilnacipran in the Management of Major Depressive Disorder: A Comprehensive Review. Curr Neuropharmacol. 2016;14(2):191-9. [Article]
- FDA Approved Drug Products: FETZIMA (levomilnacipran) extended-release capsules, for oral use (August 2023) [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- ATP-dependent translocase ABCB1
- Molecular Weight
- 141477.255 Da
References
- FDA Approved Drug Products: FETZIMA (levomilnacipran) extended-release capsules, for oral use (August 2023) [Link]
Drug created at August 01, 2013 20:17 / Updated at August 02, 2024 07:32