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Identification
- Summary
Elafibranor is a peroxisome proliferator-activated receptor agonist used to treat primary biliary cholangitis in adults with intolerance of inadequate response to ursodeoxycholic acid.
- Brand Names
- Iqirvo
- Generic Name
- Elafibranor
- DrugBank Accession Number
- DB05187
- Background
Elafibranor is a dual peroxisome proliferator-activated receptor (PPAR) α and β/δ agonist 2 that works to inhibit bile acid synthesis.4 On June 10, 2024, elafibranor was granted accelerated approval by the FDA for the treatment of primary biliary cholangitis (PBC).5
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Elafibranor (DB05187)
- Weight
- Average: 384.49
Monoisotopic: 384.139530427 - Chemical Formula
- C22H24O4S
- Synonyms
- Elafibranor
- PROPANOIC ACID, 2-(2,6-DIMETHYL-4-((1E)-3-(4-(METHYLTHIO)PHENYL)-3-OXO-1-PROPEN-1-YL)PHENOXY)-
- PROPANOIC ACID, 2-(2,6-DIMETHYL-4-(3-(4-(METHYLTHIO)PHENYL)-3-OXO-1-PROPEN-1-YL)PHENOXY)-2-METHYL-
- External IDs
- GFT 505
- GFT-505
- GFT505
Pharmacology
- Indication
Elafibranor is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have had an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA. This indication is approved under accelerated approval and is subject to change based on the determined clinical benefit of the drug in future confirmatory trials.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 Used in combination to treat Primary biliary cholangitis Regimen in combination with: Ursodeoxycholic acid (DB01586) •••••••••••• ••••• •••••••••• •••••••• •• •••• •••••••••••••••• ••••• Used in combination to treat Primary biliary cholangitis Regimen in combination with: Ursodeoxycholic acid (DB01586) •••••••••••• ••••• •••••• •• •••••••• ••••••••••••••• •••• •••••• - 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
Elafibranor inhibits bile acid synthesis.4 It was also shown to improve insulin sensitivity, glucose homeostasis, and lipid metabolism.1 In patients with PBC, elafibranor reduced the mean levels of alkaline phosphatase (ALP).4
An in vitro PPAR functional assay showed that both elafibranor and GFT1007 produced activation of PPARalpha (EC50 = 46 nM and 14 nM, respectively, and Emax = 56% and 61%, respectively, relative to reference agonists). The potency of elafibranor and GFT1007 for PPAR-alpha activation exceeded the respective potencies for PPAR-gamma and PPAR-delta activation by approximately 3- to 8-fold.4
- Mechanism of action
Proliferator-activated receptor (PPAR) is a nuclear receptor that regulates numerical cellular processes, including lipid metabolism and inflammation.1 Different subtypes of PPARs have different roles and functions, and two of these subtypes - PPAR-alpha (α) and PPAR-delta (δ) (also known as PPARβ) - have been identified as therapeutic targets for diabetes and lipid disorders.3 PPARα controls lipid flux in the liver and regulates plasma levels of triglycerides and high-density lipoprotein (HDL) cholesterol.1 PPARδ activation leads to fatty acid transport and oxidation, increased HDL levels, and improved glucose homeostasis.1 PPARα and PPARδ also mediate anti-inflammatory actions.1
While the exact mechanism of action has not been fully elucidated, elafibranor and its active metabolite (GFT1007) are dual α and β/δ agonists.2,4 The signalling pathway for PPARδ was reported to include Fibroblast Growth Factor 21 (FGF21)-dependent downregulation of CYP7A1, the key enzyme for the synthesis of bile acids from cholesterol.4
Target Actions Organism APeroxisome proliferator-activated receptor alpha agonistHumans APeroxisome proliferator-activated receptor delta agonistHumans APeroxisome proliferator-activated receptor gamma agonistHumans - Absorption
Following once-daily dosing, the steady state of elafibranor and its major active metabolite, GFT1007, was achieved within seven and fourteen days, respectively.4 The mean (SD) Cmax at steady state was 802 (443) ng/mL for elafibranor and 2058 (459) ng/mL for GFT1007.4 The mean (SD) AUC was 3758 (1749) ng x h/mL for elafibranor and 11985 (7149) ng x h/mL for GFT1007.4
Following once-daily dosing of 80 mg in patients with PBC, the median time to peak plasma concentrations (Tmax) of elafibranor and GFT1007 was 1.25 hours (range: 0.5-2 hours).4
When administered with a high-fat and high-calorie meal, Tmax was delayed by 30 minutes for elafibranor and by 1-hour for GFT1007 compared to in fasted conditions. Under fed condition, mean Cmax and AUC of elafibranor decreased by 50% and 15% respectively and mean Cmax of GFT1007 decreased by 30%, but the AUC was not affected compared to fasted conditions. The difference was not clinically meaningful.4
- Volume of distribution
The mean apparent volume of distribution (Vd/F) of elafibranor in healthy subjects was 4731 L, following a single dose of 80 mg under fasted conditions.4
- Protein binding
Elafibranor and GFT1007 were approximately 99.7% bound to plasma proteins, mostly to serum albumin.4
- Metabolism
Elafibranor is extensively metabolized to form a major active metabolite, GFT1007, the chemical structure of which has not yet been characterized. The mean systemic exposure (AUC) to GFT1007 was 3.2-fold higher than that of elafibranor at steady state. GFT3351, an acyl glucuronide conjugate, is a major inactive metabolite that consists of four stereoisomers. In vitro studies showed that elafibranor was metabolized by 15-ketoprostaglandin 13-Δ reductase (PTGR1), a cytosolic enzyme, to form GFT1007. Elafibranor was also metabolized by CYP2J2, UGT1A3, UGT1A4, and UGT2B7. GFT1007 was further metabolized by CYP2C8, UGT1A3, and UGT2B7.4
- Route of elimination
Following a single 120 mg oral dose (1.5 times the recommended dose) of 14C-radiolabelled elafibranor in healthy subjects, approximately 77.1% of the dose was recovered in feces, primarily as elafibranor (56.7% of the administered dose) and its major metabolite GFT1007 (6.08% of the administered dose). Approximately 19.3% was recovered in urine, primarily as glucuronide conjugate GFT3351 (11.8% of the administered dose). A negligible amount of unchanged elafibranor or GFT1007 was detectable in the urine. Biliary excretion of elafibranor in humans was suggested by the excretion of 60% of orally administered elafibranor in the bile of rats.4
- Half-life
Following a single 80 mg dose under fasted conditions, median elimination half-life was 70.2 hours (range 37.1 to 92.2 hours) for elafibranor, and 15.4 hours (range 9.39 to 21.7 hours) for major active metabolite GFT1007.4
- Clearance
The mean apparent total clearance (CL/F) of elafibranor was 50.0 L/h after a single 80 mg dose under fasted conditions.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
There is limited information regarding the overdosage and acute toxicity (LD50) of elafibranor.
- 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 softwareAbemaciclib The metabolism of Abemaciclib can be increased when combined with Elafibranor. Acalabrutinib The metabolism of Acalabrutinib can be increased when combined with Elafibranor. Acenocoumarol The metabolism of Acenocoumarol can be increased when combined with Elafibranor. Albendazole The metabolism of Albendazole can be increased when combined with Elafibranor. Alectinib The metabolism of Alectinib can be increased when combined with Elafibranor. - Food Interactions
- Take with or without food. A high-fat and high-calorie meal delays Tmax and decreases Cmax and AUC, but not 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.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Iqirvo Tablet, film coated 80 mg/1 Oral Ipsen Biopharmaceuticals, Inc. 2024-06-10 Not applicable US 
Categories
- ATC Codes
- A05AX06 — Elafibranor
- Drug Categories
- Acids, Acyclic
- Alimentary Tract and Metabolism
- BCRP/ABCG2 Inhibitors
- BCRP/ABCG2 Substrates
- Benzopyrans
- Bile and Liver Therapy
- Bile Therapy
- BSEP/ABCB11 Inhibitors
- Cytochrome P-450 CYP2C8 Substrates
- Cytochrome P-450 CYP3A Inducers
- Cytochrome P-450 CYP3A4 Inducers
- Cytochrome P-450 CYP3A4 Inducers (weak)
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 Substrates
- Heterocyclic Compounds, Fused-Ring
- Ketones
- PPAR alpha, agonists
- PPAR delta, agonists
- Propiophenones
- Pyrans
- UGT1A3 substrates
- UGT1A4 substrates
- UGT1A6 Inhibitors
- UGT2B7 substrates
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as retrochalcones. These are a form of normal chalcones that are structurally distinguished by the lack of oxygen functionalities at the C2'- and C6'-positions.
- Kingdom
- Organic compounds
- Super Class
- Phenylpropanoids and polyketides
- Class
- Linear 1,3-diarylpropanoids
- Sub Class
- Chalcones and dihydrochalcones
- Direct Parent
- Retrochalcones
- Alternative Parents
- Cinnamic acids and derivatives / Phenoxyacetic acid derivatives / Aryl ketones / Benzoyl derivatives / m-Xylenes / Phenol ethers / Phenoxy compounds / Thiophenol ethers / Styrenes / Alkyl aryl ethers show 8 more
- Substituents
- Acryloyl-group / Alkyl aryl ether / Alkylarylthioether / Alpha,beta-unsaturated ketone / Aromatic homomonocyclic compound / Aryl ketone / Aryl thioether / Benzenoid / Benzoyl / Carbonyl group show 23 more
- Molecular Framework
- Aromatic homomonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 2J3H5C81A5
- CAS number
- 923978-27-2
- InChI Key
- AFLFKFHDSCQHOL-IZZDOVSWSA-N
- InChI
- InChI=1S/C22H24O4S/c1-14-12-16(13-15(2)20(14)26-22(3,4)21(24)25)6-11-19(23)17-7-9-18(27-5)10-8-17/h6-13H,1-5H3,(H,24,25)/b11-6+
- IUPAC Name
- 2-{2,6-dimethyl-4-[(1E)-3-[4-(methylsulfanyl)phenyl]-3-oxoprop-1-en-1-yl]phenoxy}-2-methylpropanoic acid
- SMILES
- CSC1=CC=C(C=C1)C(=O)\C=C\C1=CC(C)=C(OC(C)(C)C(O)=O)C(C)=C1
References
- General References
- Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, Romero-Gomez M, Boursier J, Abdelmalek M, Caldwell S, Drenth J, Anstee QM, Hum D, Hanf R, Roudot A, Megnien S, Staels B, Sanyal A: Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-alpha and -delta, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology. 2016 May;150(5):1147-1159.e5. doi: 10.1053/j.gastro.2016.01.038. Epub 2016 Feb 11. [Article]
- Zhang M, Barroso E, Ruart M, Pena L, Peyman M, Aguilar-Recarte D, Montori-Grau M, Rada P, Cugat C, Montironi C, Zarei M, Jurado-Aguilar J, Camins A, Balsinde J, Valverde AM, Wahli W, Palomer X, Vazquez-Carrera M: Elafibranor upregulates the EMT-inducer S100A4 via PPARbeta/delta. Biomed Pharmacother. 2023 Nov;167:115623. doi: 10.1016/j.biopha.2023.115623. Epub 2023 Sep 30. [Article]
- Cariou B, Zair Y, Staels B, Bruckert E: Effects of the new dual PPAR alpha/delta agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care. 2011 Sep;34(9):2008-14. doi: 10.2337/dc11-0093. Epub 2011 Aug 4. [Article]
- FDA Approved Drug Products: IQIRVO (elafibranor) tablets, for oral use [Link]
- Ipsen: Ipsen’s Iqirvo® receives U.S. FDA accelerated approval as a first-in-class PPAR treatment for primary biliary cholangitis [Link]
- External Links
- PubChem Compound
- 9864881
- PubChem Substance
- 347827716
- ChemSpider
- 8040573
- BindingDB
- 50502541
- 2684941
- ChEMBL
- CHEMBL3707395
- ZINC
- ZINC000114643710
- PDBe Ligand
- MUO
- Wikipedia
- Elafibranor
- PDB Entries
- 8huq
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 data3 Active Not Recruiting Treatment Primary Biliary Cholangitis 1 somestatus stop reason just information to hide 3 Recruiting Treatment Primary Biliary Cholangitis 2 somestatus stop reason just information to hide 3 Terminated Treatment Nonalcoholic Steatohepatitis (NASH) With Fibrosis 1 somestatus stop reason just information to hide 2 Active Not Recruiting Treatment Primary Sclerosing Cholangitis (PSC) 1 somestatus stop reason just information to hide 2 Completed Treatment Atherogenic Dyslipidemia / Obesity, Abdominal 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral 80 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US11857523 No 2017-03-30 2037-03-30 US US11850223 No 2017-03-30 2037-03-30 US US11331292 No 2017-03-30 2037-03-30 US US11185519 No 2017-03-30 2037-03-30 US US7943661 No 2004-09-09 2024-09-09 US US7632870 No 2004-09-09 2024-09-09 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.000228 mg/mL ALOGPS logP 4.6 ALOGPS logP 5.87 Chemaxon logS -6.2 ALOGPS pKa (Strongest Acidic) 4 Chemaxon pKa (Strongest Basic) -4.9 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 63.6 Å2 Chemaxon Rotatable Bond Count 7 Chemaxon Refractivity 111.47 m3·mol-1 Chemaxon Polarizability 43.14 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-000l-7179000000-d443aeafa71832b02712 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0f6t-0090000000-b92649bf44b475172401 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0592-4592000000-fa14fb12f087ae87efc9 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-003r-1890000000-264993b76eef063e7a48 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0pb9-1930000000-11000462d9978f9a7f32 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-000t-3291000000-76334ceb4b30aaf5f080 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
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Use our structured and evidence-based datasets to unlock newinsights and accelerate drug research.
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Agonist
- General Function
- Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleylethanolamide, a naturally occurring lipid that regulates satiety. Receptor for peroxisome proliferators such as hypolipidemic drugs and fatty acids. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as a transcription activator for the ACOX1 and P450 genes. Transactivation activity requires heterodimerization with RXRA and is antagonized by NR2C2. May be required for the propagation of clock information to metabolic pathways regulated by PER2
- Specific Function
- DNA binding
- Gene Name
- PPARA
- Uniprot ID
- Q07869
- Uniprot Name
- Peroxisome proliferator-activated receptor alpha
- Molecular Weight
- 52224.595 Da
References
- FDA Approved Drug Products: IQIRVO (elafibranor) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Agonist
- General Function
- Ligand-activated transcription factor key mediator of energy metabolism in adipose tissues (PubMed:35675826). Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Has a preference for poly-unsaturated fatty acids, such as gamma-linoleic acid and eicosapentanoic acid. Once activated by a ligand, the receptor binds to promoter elements of target genes. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the acyl-CoA oxidase gene. Decreases expression of NPC1L1 once activated by a ligand
- Specific Function
- DNA binding
- Gene Name
- PPARD
- Uniprot ID
- Q03181
- Uniprot Name
- Peroxisome proliferator-activated receptor delta
- Molecular Weight
- 49902.99 Da
References
- FDA Approved Drug Products: IQIRVO (elafibranor) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Agonist
- General Function
- Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated pro-inflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of BMAL1 in the blood vessels (By similarity)
- Specific Function
- alpha-actinin binding
- Gene Name
- PPARG
- Uniprot ID
- P37231
- Uniprot Name
- Peroxisome proliferator-activated receptor gamma
- Molecular Weight
- 57619.58 Da
References
- FDA Approved Drug Products: IQIRVO (elafibranor) tablets, for oral use [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- NAD(P)H-dependent oxidoreductase involved in metabolic inactivation of pro- and anti-inflammatory eicosanoids: prostaglandins (PG), leukotrienes (LT) and lipoxins (LX) (PubMed:25619643). Catalyzes with high efficiency the reduction of the 13,14 double bond of 15-oxoPGs, including 15-oxo-PGE1, 15-oxo-PGE2, 15-oxo-PGF1-alpha and 15-oxo-PGF2-alpha (PubMed:25619643). Catalyzes with lower efficiency the oxidation of the hydroxyl group at C12 of LTB4 and its derivatives, converting them into biologically less active 12-oxo-LTB4 metabolites (By similarity) (PubMed:25619643). Reduces 15-oxo-LXA4 to 13,14 dihydro-15-oxo-LXA4, enhancing neutrophil recruitment at the inflammatory site (By similarity). May play a role in metabolic detoxification of alkenals and ketones. Reduces alpha,beta-unsaturated alkenals and ketones, particularly those with medium-chain length, showing highest affinity toward (2E)-decenal and (3E)-3-nonen-2-one (PubMed:25619643). May inactivate 4-hydroxy-2-nonenal, a cytotoxic lipid constituent of oxidized low-density lipoprotein particles (By similarity)
- Specific Function
- 13-lipoxin reductase activity
- Gene Name
- PTGR1
- Uniprot ID
- Q14914
- Uniprot Name
- Prostaglandin reductase 1
- Molecular Weight
- 35869.64 Da
References
- FDA Approved Drug Products: IQIRVO (elafibranor) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- Curator comments
- GFT1007, a metabolite of elafibranor, is a substrate of UGT1A3.
- General Function
- UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:15472229, PubMed:18674515, PubMed:18719240, PubMed:23288867, PubMed:23756265, PubMed:24641623). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:23756265). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol and estrone (PubMed:15472229, PubMed:18719240, PubMed:23288867). Contributes to bile acid (BA) detoxification by catalyzing the glucuronidation of BA substrates, which are natural detergents for dietary lipids absorption (PubMed:23756265). Involved in the glucuronidation of calcidiol, which is the major circulating form of vitamin D3, essential for the regulation of calcium and phosphate homeostasis (PubMed:24641623). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonists losartan, candesartan and zolarsartan, which can inhibit the effect of angiotensin II (PubMed:18674515)
- Specific Function
- enzyme binding
- Gene Name
- UGT1A3
- Uniprot ID
- P35503
- Uniprot Name
- UDP-glucuronosyltransferase 1A3
- Molecular Weight
- 60337.835 Da
References
- FDA Approved Drug Products: IQIRVO (elafibranor) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:18177842, PubMed:24641623). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:18177842). Involved in the glucuronidation of calcidiol, which is the major circulating form of vitamin D3 essential for the regulation of calcium and phosphate homeostasis (PubMed:24641623). Also glucuronidates the biologically active form of vitamin D3, calcitriol, probably leading to its biliary transport and intestinal reabsorption (PubMed:18177842)
- Specific Function
- enzyme binding
- Gene Name
- UGT1A4
- Uniprot ID
- P22310
- Uniprot Name
- UDP-glucuronosyltransferase 1A4
- Molecular Weight
- 60024.535 Da
References
- FDA Approved Drug Products: IQIRVO (elafibranor) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- GFT1007, the active metabolite of elafibranor, inhibited UGT1A6 but the clinical relevance of UGT1A6 inhibition is unknown.
- General Function
- UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 3 lacks transferase activity but acts as a negative regulator of isoform 1 (By similarity)
- Specific Function
- enzyme binding
- Gene Name
- UGT1A6
- Uniprot ID
- P19224
- Uniprot Name
- UDP-glucuronosyltransferase 1-6
- Molecular Weight
- 60750.215 Da
References
- FDA Approved Drug Products: IQIRVO (elafibranor) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- Curator comments
- GFT1007, a metabolite of elafibranor, is a substrate of UGT2B7.
- General Function
- UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:10702251, PubMed:15470161, PubMed:15472229, PubMed:17442341, PubMed:18674515, PubMed:18719240, PubMed:19022937, PubMed:23288867, PubMed:23756265, PubMed:26220143). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:15470161, PubMed:18674515, PubMed:23756265). Catalyzes the glucuronidation of endogenous steroid hormones such as androgens (epitestosterone, androsterone) and estrogens (estradiol, epiestradiol, estriol, catechol estrogens) (PubMed:15472229, PubMed:17442341, PubMed:18719240, PubMed:19022937, PubMed:2159463, PubMed:23288867, PubMed:26220143). Also regulates the levels of retinoic acid, a major metabolite of vitamin A involved in apoptosis, cellular growth and differentiation, and embryonic development (PubMed:10702251). Contributes to bile acid (BA) detoxification by catalyzing the glucuronidation of BA substrates, which are natural detergents for dietary lipids absorption (PubMed:23756265). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist losartan, caderastan and zolarsatan, drugs which can inhibit the effect of angiotensin II (PubMed:18674515). Also metabolizes mycophenolate, an immunosuppressive agent (PubMed:15470161)
- Specific Function
- glucuronosyltransferase activity
- Gene Name
- UGT2B7
- Uniprot ID
- P16662
- Uniprot Name
- UDP-glucuronosyltransferase 2B7
- Molecular Weight
- 60720.15 Da
References
- FDA Approved Drug Products: IQIRVO (elafibranor) tablets, for oral use [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
- FDA Approved Drug Products: IQIRVO (elafibranor) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- Curator comments
- GFT1007, a metabolite of elafibranor, is a substrate of CYP2C8.
- 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: IQIRVO (elafibranor) 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 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: IQIRVO (elafibranor) tablets, for oral use [Link]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Binder
- General Function
- Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
- Specific Function
- antioxidant activity
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Albumin
- Molecular Weight
- 69365.94 Da
References
- FDA Approved Drug Products: IQIRVO (elafibranor) tablets, for oral use [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- Elafibranor inhibits this transporter.
- General Function
- Catalyzes the transport of the major hydrophobic bile salts, such as taurine and glycine-conjugated cholic acid across the canalicular membrane of hepatocytes in an ATP-dependent manner, therefore participates in hepatic bile acid homeostasis and consequently to lipid homeostasis through regulation of biliary lipid secretion in a bile salts dependent manner (PubMed:15791618, PubMed:16332456, PubMed:18985798, PubMed:19228692, PubMed:20010382, PubMed:20398791, PubMed:22262466, PubMed:24711118, PubMed:29507376, PubMed:32203132). Transports taurine-conjugated bile salts more rapidly than glycine-conjugated bile salts (PubMed:16332456). Also transports non-bile acid compounds, such as pravastatin and fexofenadine in an ATP-dependent manner and may be involved in their biliary excretion (PubMed:15901796, PubMed:18245269)
- Specific Function
- ABC-type bile acid transporter activity
- Gene Name
- ABCB11
- Uniprot ID
- O95342
- Uniprot Name
- Bile salt export pump
- Molecular Weight
- 146405.83 Da
References
- FDA Approved Drug Products: IQIRVO (elafibranor) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- Curator comments
- Elafibranor inhibits this transporter. Elafibranor is also a substrate for this transporter.
- General Function
- Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- Broad substrate specificity ATP-binding cassette transporter ABCG2
- Molecular Weight
- 72313.47 Da
References
- FDA Approved Drug Products: IQIRVO (elafibranor) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- Curator comments
- GFT3351, a metabolite of elafibranor, is an inhibitor of this transporter. Elafibranor is a substrate of this transporter.
- General Function
- ATP-dependent transporter of the ATP-binding cassette (ABC) family that binds and hydrolyzes ATP to enable active transport of various substrates including many drugs, toxicants and endogenous compound across cell membranes. Transports a wide variety of conjugated organic anions such as sulfate-, glucuronide- and glutathione (GSH)-conjugates of endo- and xenobiotics substrates (PubMed:10220572, PubMed:10421658, PubMed:11500505, PubMed:16332456). Mediates hepatobiliary excretion of mono- and bis-glucuronidated bilirubin molecules and therefore play an important role in bilirubin detoxification (PubMed:10421658). Mediates also hepatobiliary excretion of others glucuronide conjugates such as 17beta-estradiol 17-glucosiduronic acid and leukotriene C4 (PubMed:11500505). Transports sulfated bile salt such as taurolithocholate sulfate (PubMed:16332456). Transports various anticancer drugs, such as anthracycline, vinca alkaloid and methotrexate and HIV-drugs such as protease inhibitors (PubMed:10220572, PubMed:11500505, PubMed:12441801). Confers resistance to several anti-cancer drugs including cisplatin, doxorubicin, epirubicin, methotrexate, etoposide and vincristine (PubMed:10220572, PubMed:11500505)
- Specific Function
- ABC-type glutathione S-conjugate transporter activity
- Gene Name
- ABCC2
- Uniprot ID
- Q92887
- Uniprot Name
- ATP-binding cassette sub-family C member 2
- Molecular Weight
- 174205.64 Da
References
- FDA Approved Drug Products: IQIRVO (elafibranor) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- GFT3351, a metabolite of elafibranor, is an inhibitor of this transporter.
- General Function
- ATP-dependent transporter of the ATP-binding cassette (ABC) family that binds and hydrolyzes ATP to enable active transport of various substrates including many drugs, toxicants and endogenous compound across cell membranes (PubMed:10359813, PubMed:11581266, PubMed:15083066). Transports glucuronide conjugates such as bilirubin diglucuronide, estradiol-17-beta-o-glucuronide and GSH conjugates such as leukotriene C4 (LTC4) (PubMed:11581266, PubMed:15083066). Transports also various bile salts (taurocholate, glycocholate, taurochenodeoxycholate-3-sulfate, taurolithocholate- 3-sulfate) (By similarity). Does not contribute substantially to bile salt physiology but provides an alternative route for the export of bile acids and glucuronides from cholestatic hepatocytes (By similarity). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can confer resistance to various anticancer drugs, methotrexate, tenoposide and etoposide, by decreasing accumulation of these drugs in cells (PubMed:10359813, PubMed:11581266)
- Specific Function
- ABC-type bile acid transporter activity
- Gene Name
- ABCC3
- Uniprot ID
- O15438
- Uniprot Name
- ATP-binding cassette sub-family C member 3
- Molecular Weight
- 169341.14 Da
References
- FDA Approved Drug Products: IQIRVO (elafibranor) tablets, for oral use [Link]
Drug created at October 21, 2007 22:24 / Updated at October 17, 2024 17:12