Ivosidenib
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Identification
- Summary
Ivosidenib is an isocitrate dehydrogenase-1 inhibitor used to treat acute myeloid leukemia and cholangiocarcinoma in adults with a susceptible IDH1 mutation.
- Brand Names
- Tibsovo
- Generic Name
- Ivosidenib
- DrugBank Accession Number
- DB14568
- Background
Ivosidenib is a first-in-class isocitrate dehydrogenase-1 (IDH1) inhibitor. IDH1 is an enzyme that is often mutated and overexpressed in some cancers, leading to aberrant cell growth and proliferation.6 Ivosidenib inhibits mutated IDH1, blocking the enzymatic activity and further differentiation of cancer cells.5
Ivosidenib was granted accelerated approval by the FDA in July 2018 for the treatment of relapsed of refractory acute myeloid leukemia in adults.5 It is currently approved to also treat newly diagnosed acute myeloid leukemia in older adults in combination azacitidine or as monotherapy, as well as locally advanced or metastatic cholangiocarcinoma and relapsed or refractory myelodysplastic syndromes in adults. The drug is only effective in patients with a susceptible IDH1 mutation.14
In February 2023, the EMA's Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion of ivosidenib and recommended it be granted marketing authorization for the treatment of acute myeloid leukemia and cholangiocarcinoma.10 It was fully approved by the EMA in May 2023.13
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 582.97
Monoisotopic: 582.1394008 - Chemical Formula
- C28H22ClF3N6O3
- Synonyms
- Ivosidenib
- External IDs
- AG-120
Pharmacology
- Indication
Ivosidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor approved for use in the US and Europe. It is indicated for the treatment of patients with a susceptible IDH1 mutation with:
Newly Diagnosed Acute Myeloid Leukemia (AML) in combination azacitidine or as monotherapy for the treatment of newly diagnosed AML in adults who have comorbidities that preclude the use of intensive induction chemotherapy.9,12 this indication is reserved for adults 75 years or older in the US.9
Relapsed or refractory AML in adults in the US.9
Locally Advanced or Metastatic Cholangiocarcinoma in adults who have been previously treated.9,12
Relapsed or Refractory Myelodysplastic Syndromes in adults.14
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 Acute myeloid leukemia (aml) Regimen in combination with: Azacitidine (DB00928) •••••••••••• ••••• •••• •••• ••••••••• ••••• •••••••••• ••• ••••••••• ••• •••••••• ••••••••• ••••••• •••••• Used in combination to treat Acute myeloid leukemia (aml) Regimen in combination with: Azacitidine (DB00928) •••••••••••• ••••• ••••• •••••••••• •••• •••• •••••••• •••••• Treatment of Acute myeloid leukemia (aml) •••••••••••• ••••• ••••• •••••••••• •••• •••• •••••••• •••••• Treatment of Locally advanced cholangiocarcinoma •••••••••••• ••••• •••••••••• •••••••• •••• •••• •••••••• •••••• Treatment of Metastatic cholangiocarcinoma •••••••••••• ••••• •••• •••• ••••••••• •••••••••• ••••••• •••••• - Contraindications & Blackbox Warnings
- Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API
- Pharmacodynamics
Ivosidenib is an antineoplastic agent that is effective in cancers with a susceptible IDH1 mutation, which indicates increased levels of oncometabolite D-2-hydroxyglutarate (D-2HG) in cancer cells.5 Ivosidenib decreases D-2HG levels in a dose-dependent manner by inhibiting the IDH1 enzyme. Ivosidenib inhibits both the mutant and wild-type IDH1 but does not inhibit IDH2.7
- Mechanism of action
Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme in the cytoplasm and peroxisomes that plays a role in many cellular processes, including mitochondrial oxidative phosphorylation, glutamine metabolism, lipogenesis, glucose sensing, and regulation of cellular redox status.1 IDH1 converts isocitrate to α-ketoglutarate (α-KG), a normal metabolite in the carboxylic acid cycle.1 Multiple cancers are associated with missense mutations in IDH1, leading to the substitution of the amino acid arginine 132 in the enzyme active site, acquired gain-of-function activity, and increased enzyme activity.5,7 IDH1 mutation results in the accumulation of D-2-hydroxyglutarate (D-2HG), an oncometabolite that is structurally similar to α-KG.1,4 D-2HG inhibits α-KG-dependent dioxygenases, including histone and DNA demethylases, which play a role in histone and DNA demethylation along with other cellular processes.4 Inhibition of these enzymes leads to histone and DNA hypermethylation and a block in cell differentiation,1 including hematopoietic differentiation.3 With histone hypermethylation, methylation-sensitive insulators cannot regulate the activation of oncogenes.2 Excess D-2HG ultimately interferes with cellular metabolism and alters epigenetic regulation towards oncogenesis.1,4
Ivosidenib inhibits the mutant IDH1 at much lower concentrations than the wild-type enzyme.9 It targets gene mutations at position R132, with R132H and R132C being the most common mutations.5 In mouse xenograft models of IDH1-mutated AML, ivosidenib caused a decrease in D-2HG levels in a dose-dependent manner and induced myeloid differentiation in vitro and in vivo.9 Ivosidenib works to inhibit histone demethylases and restore normal methylation conditions to promote cell differentiation and oncogene regulation.4
Target Actions Organism AIsocitrate dehydrogenase [NADP] cytoplasmic inhibitorHumans - Absorption
Following oral administration, ivosidenib is rapidly absorbed.7 The Cmax following a single oral dose is 4503 ng/mL in patients with relapsed or refractory AML, 4820 ng/mL in patients with newly diagnosed AML who were also treated with azacitidine, and 4060 ng/mL in patients with cholangiocarcinoma. The steady-state was reached within 14 days. The steady-state Cmax is 6551 ng/mL in patients with relapsed or refractory AML, 6145 ng/mL in patients with newly diagnosed AML who were also treated with azacitidine, and 4799 ng/mL in patients with cholangiocarcinoma. The Tmax ranges from two to three hours.9
A high-fat meal increases ivosidenib exposure.9
- Volume of distribution
The apparent volume of distribution at steady state is 403 L in patients with relapsed or refractory AML, 504 L in patients with newly diagnosed AML who were also treated with azacitidine, and 706 L in patients with cholangiocarcinoma.9
- Protein binding
In vitro, ivosidenib is 92-96% bound to plasma proteins.9
- Metabolism
Ivosidenib is predominantly metabolized by CYP3A4 via oxidation. The exact chemical structures of the metabolites formed from CYP3A4-mediated oxidation have not been fully characterized. Ivosidenib can also undergo N-dealkylation and hydrolysis as minor metabolic pathways.7,8,9
Hover over products below to view reaction partners
- Route of elimination
Following oral administration of ivosidenib, about 77% of the dose was eliminated in feces, where 67% was in the form of unchanged parent drug. About 17% of the dose was excreted in urine, where 10% was in the form of unchanged ivosidenib.9
- Half-life
The terminal half-life at steady state is 58 hours in patients with relapsed or refractory AML, 98 hours in patients with newly diagnosed AML who were also treated with azacitidine, and 129 hours in patients with cholangiocarcinoma.9
- Clearance
The apparent clearance at steady state is 5.6 L/h in patients with relapsed or refractory AML, 4.6 L/h in patients with newly diagnosed AML who were also treated with azacitidine, and 6.1 L/h in patients with cholangiocarcinoma.9
- 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
There is limited information regarding the LD50 or overdose of ivosidenib.
Ivosidenib is associated with a risk of differentiation syndrome, Guillain-Barre syndrome, and embryo-fetal toxicity.6,9
- 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 software1,2-Benzodiazepine The metabolism of 1,2-Benzodiazepine can be increased when combined with Ivosidenib. Abametapir The serum concentration of Ivosidenib can be increased when it is combined with Abametapir. Abatacept The metabolism of Ivosidenib can be increased when combined with Abatacept. Abemaciclib The metabolism of Abemaciclib can be increased when combined with Ivosidenib. Abiraterone The metabolism of Abiraterone can be increased when combined with Ivosidenib. - Food Interactions
- Do not take with or immediately after a high-fat meal. Administration of ivosidenib with a high-fat meal increases the Cmax and AUC of ivosidenib by 98 and 25%, respectively.
- Exercise caution with grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of ivosidenib. Dose adjustment may be necessary if co-administered.
- Exercise caution with St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of ivosidenib.
- Take at the same time every day.
- 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.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Tibsovo Tablet, film coated 250 mg/1 Oral Servier Pharmaceuticals LLC 2021-10-19 Not applicable US Tibsovo Tablet, film coated 250 mg/1 Oral Agios Pharmaceuticals, Inc. 2018-07-20 2024-11-30 US Tibsovo Tablet, film coated 250 mg Oral Les Laboratoires Servier 2023-05-16 Not applicable EU
Categories
- ATC Codes
- L01XX62 — Ivosidenib
- Drug Categories
- Amino Acids
- Amino Acids, Peptides, and Proteins
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Cytochrome P-450 CYP2B6 Inducers
- Cytochrome P-450 CYP2B6 Inducers (strength unknown)
- Cytochrome P-450 CYP2C8 Inducers
- Cytochrome P-450 CYP2C8 Inducers (strength unknown)
- Cytochrome P-450 CYP2C9 Inducers
- Cytochrome P-450 CYP2C9 Inducers (strength unknown)
- Cytochrome P-450 CYP3A Inducers
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Inducers
- Cytochrome P-450 CYP3A4 Inducers (strength unknown)
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 Substrates
- Enzyme Inhibitors
- Isocitrate Dehydrogenase 1 Inhibitor
- Isocitrate dehydrogenase-1 (IDH1) inhibitors
- Isocitrate Dehydrogenase-1 Inhibitors
- Moderate Risk QTc-Prolonging Agents
- Narrow Therapeutic Index Drugs
- OAT3/SLC22A8 Inhibitors
- P-glycoprotein inhibitors
- P-glycoprotein substrates
- P-glycoprotein substrates with a Narrow Therapeutic Index
- QTc Prolonging Agents
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as proline and derivatives. These are compounds containing proline or a derivative thereof resulting from reaction of proline at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Carboxylic acids and derivatives
- Sub Class
- Amino acids, peptides, and analogues
- Direct Parent
- Proline and derivatives
- Alternative Parents
- Alpha amino acid amides / Phenylacetamides / Pyrrolidinecarboxamides / Chlorobenzenes / Pyrrolidine-2-ones / Pyridines and derivatives / Aryl chlorides / Aryl fluorides / Imidolactams / Tertiary carboxylic acid amides show 11 more
- Substituents
- 2-pyrrolidone / Alkyl fluoride / Alkyl halide / Alpha-amino acid amide / Aromatic heteromonocyclic compound / Aryl chloride / Aryl fluoride / Aryl halide / Azacycle / Benzenoid show 30 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- Q2PCN8MAM6
- CAS number
- 1448347-49-6
- InChI Key
- WIJZXSAJMHAVGX-DHLKQENFSA-N
- InChI
- InChI=1S/C28H22ClF3N6O3/c29-21-4-2-1-3-20(21)25(26(40)36-18-11-28(31,32)12-18)37(19-10-17(30)14-34-15-19)27(41)22-5-6-24(39)38(22)23-9-16(13-33)7-8-35-23/h1-4,7-10,14-15,18,22,25H,5-6,11-12H2,(H,36,40)/t22-,25-/m0/s1
- IUPAC Name
- (2S)-2-(2-chlorophenyl)-2-{1-[(2S)-1-(4-cyanopyridin-2-yl)-5-oxopyrrolidin-2-yl]-N-(5-fluoropyridin-3-yl)formamido}-N-(3,3-difluorocyclobutyl)acetamide
- SMILES
- [H][C@@](N(C(=O)[C@]1([H])CCC(=O)N1C1=NC=CC(=C1)C#N)C1=CC(F)=CN=C1)(C(=O)NC1CC(F)(F)C1)C1=C(Cl)C=CC=C1
References
- General References
- Mondesir J, Willekens C, Touat M, de Botton S: IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives. J Blood Med. 2016 Sep 2;7:171-80. doi: 10.2147/JBM.S70716. eCollection 2016. [Article]
- Flavahan WA, Drier Y, Liau BB, Gillespie SM, Venteicher AS, Stemmer-Rachamimov AO, Suva ML, Bernstein BE: Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature. 2016 Jan 7;529(7584):110-4. doi: 10.1038/nature16490. Epub 2015 Dec 23. [Article]
- Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF, Tallman MS, Sun Z, Wolniak K, Peeters JK, Liu W, Choe SE, Fantin VR, Paietta E, Lowenberg B, Licht JD, Godley LA, Delwel R, Valk PJ, Thompson CB, Levine RL, Melnick A: Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010 Dec 14;18(6):553-67. doi: 10.1016/j.ccr.2010.11.015. Epub 2010 Dec 9. [Article]
- Popovici-Muller J, Lemieux RM, Artin E, Saunders JO, Salituro FG, Travins J, Cianchetta G, Cai Z, Zhou D, Cui D, Chen P, Straley K, Tobin E, Wang F, David MD, Penard-Lacronique V, Quivoron C, Saada V, de Botton S, Gross S, Dang L, Yang H, Utley L, Chen Y, Kim H, Jin S, Gu Z, Yao G, Luo Z, Lv X, Fang C, Yan L, Olaharski A, Silverman L, Biller S, Su SM, Yen K: Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers. ACS Med Chem Lett. 2018 Jan 19;9(4):300-305. doi: 10.1021/acsmedchemlett.7b00421. eCollection 2018 Apr 12. [Article]
- Merchant SL, Culos K, Wyatt H: Ivosidenib: IDH1 Inhibitor for the Treatment of Acute Myeloid Leukemia. J Adv Pract Oncol. 2019 Jul;10(5):494-500. doi: 10.6004/jadpro.2019.10.5.7. Epub 2019 Jul 1. [Article]
- Authors unspecified: Ivosidenib . [Article]
- Dhillon S: Ivosidenib: First Global Approval. Drugs. 2018 Sep;78(14):1509-1516. doi: 10.1007/s40265-018-0978-3. [Article]
- Prakash C, Fan B, Altaf S, Agresta S, Liu H, Yang H: Pharmacokinetics, absorption, metabolism, and excretion of [(14)C]ivosidenib (AG-120) in healthy male subjects. Cancer Chemother Pharmacol. 2019 May;83(5):837-848. doi: 10.1007/s00280-019-03793-7. Epub 2019 Feb 13. [Article]
- FDA Approved Drug Products: TIBSOVO (ivosidenib) tablets, for oral use [Link]
- CHMP Summary of Positive Opinion: Tibsovo (ivosidenib) [Link]
- CHMP Summary of Positive Opinion: Tidhesco (ivosidenib) [Link]
- EMA Approved Drug Products: Tibsovo (ivosidenib) Oral Tablets [Link]
- PR Newswire: Servier receives European Commission approval of Tibsovo® (ivosidenib tablets) in IDH1-mutated Acute Myeloid Leukemia and IDH1-mutated Cholangiocarcinoma [Link]
- FDA Approved Drug Products: TIBSOVO® (ivosidenib tablets), for oral use (October 2023) [Link]
- External Links
- ChemSpider
- 38772333
- BindingDB
- 363689
- 2049873
- ChEBI
- 145430
- ChEMBL
- CHEMBL3989958
- ZINC
- ZINC000205136523
- Wikipedia
- Ivosidenib
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 Approved for Marketing Not Available Acute Myeloid Leukemia / Relapsed Adult Acute Myeloid Leukemia / Relapsed Pediatric AML 1 somestatus stop reason just information to hide Not Available Recruiting Not Available Acute Myeloid Leukemia 1 somestatus stop reason just information to hide Not Available Recruiting Treatment Acute Myeloid Leukemia / Drug Relapse / Refractory 1 somestatus stop reason just information to hide 3 Active Not Recruiting Treatment Acute Myeloid Leukemia / Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome / Newly Diagnosed Acute Myeloid Leukemia (AML) / Treatment Naive AML 1 somestatus stop reason just information to hide 3 Active Not Recruiting Treatment Acute Myeloid Leukemia / Myelodysplastic Syndrome With Excess Blasts-2 (MDS-EB-2) 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral 250 mg Tablet, film coated Oral 250 mg/1 Tablet, multilayer, extended release Oral 250 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9474779 No 2016-10-25 2033-08-19 US US9850277 No 2017-12-26 2033-01-18 US US9968595 No 2018-05-15 2035-03-13 US US10449184 No 2019-10-22 2035-03-13 US US10610125 No 2020-04-07 2030-06-21 US US10799490 No 2020-10-13 2035-03-13 US US10980788 No 2021-04-20 2039-06-07 US US10717764 No 2020-07-21 2033-01-18 US US10653710 No 2020-05-19 2036-10-18 US US11667673 No 2013-01-18 2033-01-18 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility <1 mg/mL https://www.selleck.cn/msds/MSDS_S8206.pdf - Predicted Properties
Property Value Source Water Solubility 0.0208 mg/mL ALOGPS logP 2.52 ALOGPS logP 3.01 Chemaxon logS -4.4 ALOGPS pKa (Strongest Acidic) 12.14 Chemaxon pKa (Strongest Basic) 1.81 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 6 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 119.29 Å2 Chemaxon Rotatable Bond Count 7 Chemaxon Refractivity 139.33 m3·mol-1 Chemaxon Polarizability 53.42 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- Curator comments
- Ivosidenib inhibits both the wild-type and mutant forms of IDH1 with varying affinities.
- General Function
- Catalyzes the NADP(+)-dependent oxidative decarboxylation of isocitrate (D-threo-isocitrate) to 2-ketoglutarate (2-oxoglutarate), which is required by other enzymes such as the phytanoyl-CoA dioxygenase (PubMed:10521434, PubMed:19935646). Plays a critical role in the generation of NADPH, an important cofactor in many biosynthesis pathways (PubMed:10521434). May act as a corneal epithelial crystallin and may be involved in maintaining corneal epithelial transparency (By similarity)
- Specific Function
- cadherin binding
- Gene Name
- IDH1
- Uniprot ID
- O75874
- Uniprot Name
- Isocitrate dehydrogenase [NADP] cytoplasmic
- Molecular Weight
- 46659.005 Da
References
- Megias-Vericat JE, Ballesta-Lopez O, Barragan E, Montesinos P: IDH1-mutated relapsed or refractory AML: current challenges and future prospects. Blood Lymphat Cancer. 2019 Jun 27;9:19-32. doi: 10.2147/BLCTT.S177913. eCollection 2019. [Article]
- Merchant SL, Culos K, Wyatt H: Ivosidenib: IDH1 Inhibitor for the Treatment of Acute Myeloid Leukemia. J Adv Pract Oncol. 2019 Jul;10(5):494-500. doi: 10.6004/jadpro.2019.10.5.7. Epub 2019 Jul 1. [Article]
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- FDA Approved Drug Products: TIBSOVO (ivosidenib) tablets, for oral use [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInducer
- 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
- Prakash C, Fan B, Altaf S, Agresta S, Liu H, Yang H: Pharmacokinetics, absorption, metabolism, and excretion of [(14)C]ivosidenib (AG-120) in healthy male subjects. Cancer Chemother Pharmacol. 2019 May;83(5):837-848. doi: 10.1007/s00280-019-03793-7. Epub 2019 Feb 13. [Article]
- FDA Approved Drug Products: TIBSOVO (ivosidenib) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inducer
- 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: TIBSOVO (ivosidenib) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inducer
- Curator comments
- There are limited data in the literature supporting this enzyme action, however the FDA label states that ivosidenib may induce CYP2C9.
- 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: TIBSOVO (ivosidenib) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inducer
- 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: TIBSOVO (ivosidenib) tablets, for oral use [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- 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: TIBSOVO (ivosidenib) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Functions as an organic anion/dicarboxylate exchanger that couples organic anion uptake indirectly to the sodium gradient (PubMed:14586168, PubMed:15644426, PubMed:15846473, PubMed:16455804, PubMed:31553721). Transports organic anions such as estrone 3-sulfate (E1S) and urate in exchange for dicarboxylates such as glutarate or ketoglutarate (2-oxoglutarate) (PubMed:14586168, PubMed:15846473, PubMed:15864504, PubMed:22108572, PubMed:23832370). Plays an important role in the excretion of endogenous and exogenous organic anions, especially from the kidney and the brain (PubMed:11306713, PubMed:14586168, PubMed:15846473). E1S transport is pH- and chloride-dependent and may also involve E1S/cGMP exchange (PubMed:26377792). Responsible for the transport of prostaglandin E2 (PGE2) and prostaglandin F2(alpha) (PGF2(alpha)) in the basolateral side of the renal tubule (PubMed:11907186). Involved in the transport of neuroactive tryptophan metabolites kynurenate and xanthurenate (PubMed:22108572, PubMed:23832370). Functions as a biopterin transporters involved in the uptake and the secretion of coenzymes tetrahydrobiopterin (BH4), dihydrobiopterin (BH2) and sepiapterin to urine, thereby determining baseline levels of blood biopterins (PubMed:28534121). May be involved in the basolateral transport of steviol, a metabolite of the popular sugar substitute stevioside (PubMed:15644426). May participate in the detoxification/ renal excretion of drugs and xenobiotics, such as the histamine H(2)-receptor antagonists fexofenadine and cimetidine, the antibiotic benzylpenicillin (PCG), the anionic herbicide 2,4-dichloro-phenoxyacetate (2,4-D), the diagnostic agent p-aminohippurate (PAH), the antiviral acyclovir (ACV), and the mycotoxin ochratoxin (OTA), by transporting these exogenous organic anions across the cell membrane in exchange for dicarboxylates such as 2-oxoglutarate (PubMed:11669456, PubMed:15846473, PubMed:16455804). Contributes to the renal uptake of potent uremic toxins (indoxyl sulfate (IS), indole acetate (IA), hippurate/N-benzoylglycine (HA) and 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF)), pravastatin, PCG, E1S and dehydroepiandrosterone sulfate (DHEAS), and is partly involved in the renal uptake of temocaprilat (an angiotensin-converting enzyme (ACE) inhibitor) (PubMed:14675047). May contribute to the release of cortisol in the adrenals (PubMed:15864504). Involved in one of the detoxification systems on the choroid plexus (CP), removes substrates such as E1S or taurocholate (TC), PCG, 2,4-D and PAH, from the cerebrospinal fluid (CSF) to the blood for eventual excretion in urine and bile (By similarity). Also contributes to the uptake of several other organic compounds such as the prostanoids prostaglandin E(2) and prostaglandin F(2-alpha), L-carnitine, and the therapeutic drugs allopurinol, 6-mercaptopurine (6-MP) and 5-fluorouracil (5-FU) (By similarity). Mediates the transport of PAH, PCG, and the statins pravastatin and pitavastatin, from the cerebrum into the blood circulation across the blood-brain barrier (BBB). In summary, plays a role in the efflux of drugs and xenobiotics, helping reduce their undesired toxicological effects on the body (By similarity)
- Specific Function
- organic anion transmembrane transporter activity
- Gene Name
- SLC22A8
- Uniprot ID
- Q8TCC7
- Uniprot Name
- Organic anion transporter 3
- Molecular Weight
- 59855.585 Da
References
- FDA Approved Drug Products: TIBSOVO (ivosidenib) tablets, for oral use [Link]
Drug created at July 20, 2018 16:42 / Updated at November 24, 2023 04:34