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Identification
- Summary
Ixazomib is a proteasome inhibitor used with other medications to treat multiple myeloma in patients who have received one other therapy already.
- Brand Names
- Ninlaro
- Generic Name
- Ixazomib
- DrugBank Accession Number
- DB09570
- Background
Ixazomib is a reversible proteasome inhibitor. Because it is a modified peptide boronic acid with one chiral center,4 it is considered a boronate proteasome inhibitor.1 More than 99% of the drug compound is the R-enantiomer.4
Ixazomib was approved by the FDA on November 20, 2015, making it the first oral proteasome inhibitor approved in the US.2 It was later approved by Health Canada on August 3, 2016,6 and by the EMA on November 21, 2016.7 It was also investigated in other hematological malignancies as well as other conditions, such as systemic light chain (AL) amyloidosis, graft-versus-host disease, and lupus nephritis.3
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Ixazomib (DB09570)
- Weight
- Average: 361.03
Monoisotopic: 360.081492 - Chemical Formula
- C14H19BCl2N2O4
- Synonyms
- ((1R)-1-((2,5-DICHLOROBENZAMIDO)ACETAMIDO)-3-METHYLBUTYL)BORONIC ACID
- 2-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diacetic acid
- BORONIC ACID, B-((1R)-1-((2-((2,5-DICHLOROBENZOYL)AMINO)ACETYL)AMINO)-3-METHYLBUTYL)-
- Ixazomib
- External IDs
- MLN 2238
- MLN-2238
- MLN2238
Pharmacology
- Indication
Ixazomib is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.5,6,7
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 Used in combination to treat Multiple myeloma Regimen in combination with: Lenalidomide (DB00480), Dexamethasone (DB01234) •••••••••••• ••••• •• ••••• ••• ••••• ••••••• - Contraindications & Blackbox Warnings
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Ixazomib exerts antimyeloma effects with time-dependent reversible proteasome inhibition.1 Ixazomib induced apoptosis of multiple myeloma cell lines in vitro.2 Ixazomib demonstrated in vitro cytotoxicity against myeloma cells from patients who had relapsed after multiple prior therapies, including bortezomib, lenalidomide, and dexamethasone. The combination of ixazomib and lenalidomide demonstrated synergistic cytotoxic effects in multiple myeloma cell lines. In vivo, ixazomib demonstrated antitumour activity in a mouse multiple myeloma tumour xenograft model.5
Studies show that ixazomib exhibits an antiangiogenic activity and blocks osteoclastogenesis and osteoclast reabsorption.1
- Mechanism of action
The ubiquitin-proteasome signalling pathway regulates cellular homeostasis and survival: It promotes protein degradation, activates the transcriptional factor nuclear factor (NF)-κB to upregulate the expression of growth and angiogenic factors, and blocks apoptosis. Made up of identical alpha (α)- and beta (β)-rings, the 20S proteasome catalytic core is part of the proteasome.1
Ixazomib is a selective, potent, and reversible inhibitor of the 20S proteasome. It preferentially binds to the β5 chymotrypsin-like proteolytic site with a half-maximal inhibitory concentration (IC50) value of 3.4 nmol/L.4,5 At higher concentrations, ixazomib may inhibit the caspase-like (β1) and trypsin-like (β2) proteolytic sites.1
Target Actions Organism UProteasome subunit beta type-5 inhibitorHumans - Absorption
Upon oral administration, ixazomib is rapidly absorbed 4 with a Tmax of one hour.5 Based on population pharmacokinetic (PK) analysis, the mean absolute oral bioavailability was 58%. Ixazomib area under the curve (AUC) increases in a dose-proportional manner over a dose range of 0.2 to 10.6 mg. A food effect study conducted in patients with a single 4 mg dose of ixazomib showed that a high-fat meal decreased ixazomib AUC by 28% and Cmax by 69%.5
- Volume of distribution
The steady-state volume of distribution is 543 L.5
- Protein binding
Ixazomib is 99% bound to plasma proteins and distributes into red blood cells with a blood-to-plasma ratio of 10.5
- Metabolism
After the oral administration of a radiolabeled dose, ixazomib represented 70% of total drug-related material in plasma.5 Ixazomib undergoes both CYP- and non-CYP-mediated metabolism, which is reported to be the major drug clearance mechanism.4 The major biotransformation pathways include hydrolysis, deboronation, and N-dealkylation, with drug metabolites not expected to retain pharmacological activity.4
At clinically relevant ixazomib concentrations, in vitro studies using human cDNA-expressed cytochrome P450 isozymes showed that no specific CYP isozyme predominantly contributes to ixazomib metabolism. At higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms with estimated relative contributions of 3A4 (42%), 1A2 (26%), 2B6 (16%), 2C8 (6%), 2D6 (5%), 2C19 (5%) and 2C9 (< 1%).5
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- Route of elimination
After administration of a single oral dose of 14C-ixazomib to 5 patients with advanced cancer, 62% of the administered radioactivity was excreted in urine and 22% in the feces. Unchanged ixazomib accounted for < 3.5% of the administered dose recovered in urine.5
Following weekly oral dosing, the accumulation ratio was determined to be two-fold.5
- Half-life
The terminal half-life (t1/2) of ixazomib was 9.5 days based on a population PK analysis.5
- Clearance
Based on a population PK analysis, systemic clearance was approximately 1.9 L/hr with inter-individual variability of 44%.5
- 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
Overdosage, including fatal overdosage, has been reported in patients taking ixazomib. Manifestations of overdosage include adverse reactions reported at the recommended dosage, including severe nausea, vomiting, diarrhea, aspiration pneumonia, multiple organ failure and death. There is no known specific antidote for ixazomib overdose and ixazomib is not dialyzable. In the event of an overdose, monitor the patient closely for adverse reactions and provide appropriate supportive care.5,6
- 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 Ixazomib which could result in a higher serum level. Abametapir The serum concentration of Ixazomib can be increased when it is combined with Abametapir. Abatacept The metabolism of Ixazomib can be increased when combined with Abatacept. Acalabrutinib The metabolism of Ixazomib can be decreased when combined with Acalabrutinib. Aceclofenac Aceclofenac may decrease the excretion rate of Ixazomib which could result in a higher serum level. - Food Interactions
- Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of ixazomib.
- Take on an empty stomach. Food increases the absorption of ixazomib, take ixazomib dose at least one hour before and at least two hours after 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 Ixazomib citrate 46CWK97Z3K 1239908-20-3 MBOMYENWWXQSNW-AWEZNQCLSA-N - International/Other Brands
- Ninlaro
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Ninlaro Capsule 3 mg/1 Oral Takeda Pharmaceuticals America, Inc. 2015-11-20 Not applicable US 
Ninlaro Capsule 3 mg/1 Oral Takeda Pharmaceuticals America, Inc. 2015-11-20 2023-10-31 US Ninlaro Capsule 2.3 mg Oral Takeda Pharma A/S 2021-02-10 Not applicable EU 
Ninlaro Capsule 2.3 mg Oral Takeda 2016-09-21 Not applicable Canada 
Ninlaro Capsule 4 mg/1 Oral Takeda Pharmaceuticals America, Inc. 2015-11-20 Not applicable US
Categories
- ATC Codes
- L01XG03 — Ixazomib
- Drug Categories
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Cytochrome P-450 CYP1A2 Substrates
- Cytochrome P-450 CYP1A2 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP2B6 Substrates
- Cytochrome P-450 CYP2B6 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP2C19 Substrates
- Cytochrome P-450 CYP2C19 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP2C8 Substrates
- Cytochrome P-450 CYP2C8 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP2C9 Substrates
- Cytochrome P-450 CYP2C9 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP2D6 Substrates
- Cytochrome P-450 CYP2D6 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Substrates
- Drugs that are Mainly Renally Excreted
- Narrow Therapeutic Index Drugs
- P-glycoprotein substrates
- P-glycoprotein substrates with a Narrow Therapeutic Index
- Proteasome Inhibitors
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as hippuric acids and derivatives. These are compounds containing a hippuric acid or a derivative, with a structure characterized the presence of a benzoyl group linked to the N-terminal of a glycine.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Benzoic acids and derivatives
- Direct Parent
- Hippuric acids and derivatives
- Alternative Parents
- N-acyl-alpha amino acids and derivatives / Alpha amino acid amides / 2-halobenzoic acids and derivatives / 3-halobenzoic acids and derivatives / Benzoyl derivatives / Dichlorobenzenes / Aryl chlorides / Vinylogous halides / Secondary carboxylic acid amides / Boronic acids show 8 more
- Substituents
- 1,4-dichlorobenzene / 2-halobenzoic acid or derivatives / 3-halobenzoic acid or derivatives / Alkylborane / Alpha-amino acid amide / Alpha-amino acid or derivatives / Aromatic homomonocyclic compound / Aryl chloride / Aryl halide / Benzoyl show 26 more
- Molecular Framework
- Aromatic homomonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 71050168A2
- CAS number
- 1072833-77-2
- InChI Key
- MXAYKZJJDUDWDS-LBPRGKRZSA-N
- InChI
- InChI=1S/C14H19BCl2N2O4/c1-8(2)5-12(15(22)23)19-13(20)7-18-14(21)10-6-9(16)3-4-11(10)17/h3-4,6,8,12,22-23H,5,7H2,1-2H3,(H,18,21)(H,19,20)/t12-/m0/s1
- IUPAC Name
- [(1R)-1-{2-[(2,5-dichlorophenyl)formamido]acetamido}-3-methylbutyl]boronic acid
- SMILES
- CC(C)C[C@H](NC(=O)CNC(=O)C1=CC(Cl)=CC=C1Cl)B(O)O
References
- General References
- Offidani M, Corvatta L, Caraffa P, Gentili S, Maracci L, Leoni P: An evidence-based review of ixazomib citrate and its potential in the treatment of newly diagnosed multiple myeloma. Onco Targets Ther. 2014 Sep 29;7:1793-800. doi: 10.2147/OTT.S49187. eCollection 2014. [Article]
- Raedler LA: Ninlaro (Ixazomib): First Oral Proteasome Inhibitor Approved for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma. Am Health Drug Benefits. 2016 Mar;9(Spec Feature):102-5. [Article]
- Shirley M: Ixazomib: First Global Approval. Drugs. 2016 Mar;76(3):405-11. doi: 10.1007/s40265-016-0548-5. [Article]
- Gupta N, Hanley MJ, Xia C, Labotka R, Harvey RD, Venkatakrishnan K: Clinical Pharmacology of Ixazomib: The First Oral Proteasome Inhibitor. Clin Pharmacokinet. 2019 Apr;58(4):431-449. doi: 10.1007/s40262-018-0702-1. [Article]
- FDA Approved Drug Products: NINLARO (ixazomib) capsules, for oral use (July 2024) [Link]
- Health Canada Approved Drug Products: NINLARO (Ixazomib) Oral Capsules [Link]
- EMA Approved Drug Products: NINLARO (Ixazomib) Oral Capsules [Link]
- External Links
- KEGG Drug
- D10130
- PubChem Compound
- 25183872
- PubChem Substance
- 310265228
- ChemSpider
- 25027391
- BindingDB
- 50398609
- 1723735
- ChEBI
- 90942
- ChEMBL
- CHEMBL2141296
- ZINC
- ZINC000169946773
- PDBe Ligand
- 6V8
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Ixazomib
- PDB Entries
- 5lf7 / 7q11 / 8qyf
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 Relapsed/Refractory Multiple Myeloma (RRMM) 2 somestatus stop reason just information to hide Not Available Recruiting Treatment Maintenances / Overall Survivals / Progression Free Survival 1 somestatus stop reason just information to hide Not Available Unknown Status Not Available Relapsed/Refractory Multiple Myeloma (RRMM) 1 somestatus stop reason just information to hide 4 Active Not Recruiting Treatment Multiple Myeloma (MM) 1 somestatus stop reason just information to hide 4 Completed Treatment Multiple Myeloma (MM) 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 2.3 mg/1 Capsule Oral 3 mg/1 Capsule Oral 3.0 MG Capsule Oral 4 mg/1 Capsule Oral 4.0 MG Capsule Oral 2.3 mg Capsule Oral 3 mg Capsule Oral 4 mg Capsule Oral 3.29 Mg Capsule Oral 4.3 Mg Capsule Oral 5.7 Mg Capsule, coated Oral 2.3 mg Capsule, coated Oral 3 mg Capsule, coated Oral 4 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8871745 No 2014-10-28 2027-08-06 US US8530694 No 2013-09-10 2027-08-06 US US7442830 No 2008-10-28 2027-08-06 US US9175017 No 2015-11-03 2029-06-16 US US8003819 No 2011-08-23 2027-08-06 US US9233115 No 2016-01-12 2024-08-12 US US8546608 No 2013-10-01 2024-08-12 US US7687662 No 2010-03-30 2027-08-06 US US8859504 No 2014-10-14 2029-06-16 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0124 mg/mL ALOGPS logP 2.06 ALOGPS logP 2.57 Chemaxon logS -4.5 ALOGPS pKa (Strongest Acidic) 8.64 Chemaxon pKa (Strongest Basic) -1.8 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 4 Chemaxon Polar Surface Area 98.66 Å2 Chemaxon Rotatable Bond Count 7 Chemaxon Refractivity 84.56 m3·mol-1 Chemaxon Polarizability 36.3 Å3 Chemaxon Number of Rings 1 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
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB5 displays a chymotrypsin-like activity
- Specific Function
- Endopeptidase activity
- Gene Name
- PSMB5
- Uniprot ID
- P28074
- Uniprot Name
- Proteasome subunit beta type-5
- Molecular Weight
- 28480.01 Da
References
- Gupta N, Hanley MJ, Xia C, Labotka R, Harvey RD, Venkatakrishnan K: Clinical Pharmacology of Ixazomib: The First Oral Proteasome Inhibitor. Clin Pharmacokinet. 2019 Apr;58(4):431-449. doi: 10.1007/s40262-018-0702-1. [Article]
- Raedler LA: Ninlaro (Ixazomib): First Oral Proteasome Inhibitor Approved for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma. Am Health Drug Benefits. 2016 Mar;9(Spec Feature):102-5. [Article]
- FDA Approved Drug Products: NINLARO (ixazomib) capsules, for oral use (July 2024) [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: NINLARO (ixazomib) capsules, for oral use (July 2024) [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:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). 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:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:11555828, PubMed:12865317). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2 (PubMed:11555828, PubMed:12865317). Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). May act as a major enzyme for all-trans retinoic acid biosynthesis in the liver. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer (PubMed:19965576). Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA (PubMed:9435160). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin (PubMed:14725854). Metabolizes caffeine via N3-demethylation (Probable)
- Specific Function
- Aromatase activity
- Gene Name
- CYP1A2
- Uniprot ID
- P05177
- Uniprot Name
- Cytochrome P450 1A2
- Molecular Weight
- 58406.915 Da
References
- Gupta N, Diderichsen PM, Hanley MJ, Berg D, van de Velde H, Harvey RD, Venkatakrishnan K: Population Pharmacokinetic Analysis of Ixazomib, an Oral Proteasome Inhibitor, Including Data from the Phase III TOURMALINE-MM1 Study to Inform Labelling. Clin Pharmacokinet. 2017 Nov;56(11):1355-1368. doi: 10.1007/s40262-017-0526-4. [Article]
- Kumar SK, Buadi FK, LaPlant B, Halvorson A, Leung N, Kapoor P, Dingli D, Gertz MA, Go RS, Bergsagel PL, Lin Y, Dispenzieri A, Hwa YL, Fonder A, Hobbs M, Fonseca R, Hayman SR, Stewart AK, Lust JA, Mikhael J, Gonsalves W, Reeder C, Skacel T, Rajkumar SV, Lacy MQ: Phase 1/2 trial of ixazomib, cyclophosphamide and dexamethasone in patients with previously untreated symptomatic multiple myeloma. Blood Cancer J. 2018 Jul 30;8(8):70. doi: 10.1038/s41408-018-0106-3. [Article]
- FDA Approved Drug Products: NINLARO (ixazomib) capsules, for oral use (July 2024) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of endocannabinoids and steroids (PubMed:12865317, PubMed:21289075). 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 epoxidation of double bonds of arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:21289075). Hydroxylates steroid hormones, including testosterone at C-16 and estrogens at C-2 (PubMed:12865317, PubMed:21289075). Plays a role in the oxidative metabolism of xenobiotics, including plant lipids and drugs (PubMed:11695850, PubMed:22909231). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850)
- Specific Function
- Anandamide 11,12 epoxidase activity
- Gene Name
- CYP2B6
- Uniprot ID
- P20813
- Uniprot Name
- Cytochrome P450 2B6
- Molecular Weight
- 56277.81 Da
References
- FDA Approved Drug Products: NINLARO (ixazomib) capsules, for oral use (July 2024) [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
- FDA Approved Drug Products: NINLARO (ixazomib) capsules, for oral use (July 2024) [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
- FDA Approved Drug Products: NINLARO (ixazomib) capsules, for oral use (July 2024) [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
- FDA Approved Drug Products: NINLARO (ixazomib) capsules, for oral use (July 2024) [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 and steroids (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). 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:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:15766564, PubMed:19965576, PubMed:7574697, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9435160, PubMed:9866708). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031)
- Specific Function
- (r)-limonene 6-monooxygenase activity
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- FDA Approved Drug Products: NINLARO (ixazomib) capsules, for oral use (July 2024) [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- Curator comments
- Ixazomib is a low affinity substrate of P-glycoprotein.
- 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
- Gupta N, Hanley MJ, Xia C, Labotka R, Harvey RD, Venkatakrishnan K: Clinical Pharmacology of Ixazomib: The First Oral Proteasome Inhibitor. Clin Pharmacokinet. 2019 Apr;58(4):431-449. doi: 10.1007/s40262-018-0702-1. [Article]
- FDA Approved Drug Products: NINLARO (ixazomib) capsules, for oral use (July 2024) [Link]
Drug created at November 30, 2015 19:10 / Updated at September 16, 2024 01:24