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Identification
- Summary
Vadadustat is an oral hypoxia-inducible factor prolyl-hydroxylase inhibitor used to treat symptomatic anemia associated with chronic kidney disease in adults on chronic maintenance dialysis.
- Brand Names
- Vafseo
- Generic Name
- Vadadustat
- DrugBank Accession Number
- DB12255
- Background
One of the most common symptoms of advanced renal disease is anemia, caused primarily by the inability of the kidney to respond to anemic conditions with a corresponding increase in erythropoietin (EPO) production.3 The treatment of anemia associated with chronic kidney disease (CKD) has traditionally involved the administration of exogenous erythropoiesis-stimulating agents (ESAs), such as darbepoetin alfa, to counter the decrease in endogenous EPO production. While efficacious, the overuse of ESAs has been associated with cardiovascular complications, progression of CKD, and increases in overall mortality.3
A relatively new and alternative treatment option for patients with anemia associated with CKD is the use of small molecule inhibitors of hypoxia-inducible factor prolyl-hydroxylase (HIF-PH). These agents inhibit prolyl-hydroxylase domain oxygen sensors, mimicking hypoxic conditions and activating hypoxia-inducible factors. These transcription factors serve a multitude of roles, including the stimulation of erythropoiesis.3
Vadadustat is an orally administered inhibitor of HIF-PH with a safety and efficacy profile non-inferior to darbepoetin alfa for the treatment of anemia in patients with CKD undergoing dialysis.1,2 It was first approved in Japan in 2020,10 and in April 2023, it was approved by the EMA for the treatment of symptomatic anemia associated with CKD in adults on chronic maintenance dialysis.5,6,7 Vadadustat was approved by the FDA in March 2024.10
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Vadadustat (DB12255)
- Weight
- Average: 306.7
Monoisotopic: 306.0407345 - Chemical Formula
- C14H11ClN2O4
- Synonyms
- Glycine, N-((5-(3-chlorophenyl)-3-hydroxy-2-pyridinyl)carbonyl)-
- N-(5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl)glycine
- Vadadustat
- External IDs
- AKB 6548
- AKB-6548
- B-506
- B506
- PG-1016548
- PG1016548
Pharmacology
- Indication
Vadadustat is indicated for the treatment of symptomatic anemia associated with chronic kidney disease (CKD) in adults on chronic maintenance dialysis.6,9
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 Treatment of Anemia associated with chronic kidney disease (ckd) •••••••••••• ••••• ••••••• ••••••••••• •••••••• •••••• Treatment of Anemia associated with chronic kidney disease (ckd) •••••••••••• ••••• ••••••••• •••••••• ••• •• ••••• ••••• •••••• •••••• - Contraindications & Blackbox Warnings
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The use of vadadustat was compared to darbepoetin alfa for the treatment of anemia in adult patients with dialysis-dependent chronic kidney disease. Vadadustat was non-inferior to darbepoetin alfa and met the primary hemoglobin level endpoint. In healthy subjects given 600 mg to 1200 mg of vadadustat, the use of this drug was not associated with clinically significant QTc prolongation. Compared to darbepoetin alfa, patients with dialysis-dependent chronic kidney disease treated with vadadustat have similar risks for death, myocardial infarction and stroke. The use of vadadustat may also lead to the development of thromboembolic events, hepatic impairment, hepatotoxicity, convulsions, as well as an increase in blood pressure.6
- Mechanism of action
Hypoxia-inducible factors (HIFs) are transcription factors responsible for cellular survival under hypoxic conditions. They regulate a number of processes including angiogenesis, cell growth and differentiation, various metabolic processes, and erythropoiesis.3 Under normoxic conditions, HIFs are degraded via hydroxylation by prolyl-hydroxylase dioxygenases.
Vadadustat is an inhibitor of HIF-prolyl-hydroxylases (HIF-PHI), that facilitates increased HIF activity in the absence of hypoxic conditions.3,4 The increased levels of HIF prompted by vadadustat stimulate endogenous erythropoietin production, increasing iron mobilization and contributing to the gradual rise of hemoglobin levels and the correction of iron metabolism.6 In patients with anemia of chronic kidney disease, in whom normal erythropoiesis is dysfunctional, this leads to the correction of anemia.
Target Actions Organism AEgl nine homolog 1 inhibitorHumans AProlyl hydroxylase EGLN2 inhibitorHumans AProlyl hydroxylase EGLN3 inhibitorHumans UHypoxia-inducible factor 1-alpha stabilizationHumans UEndothelial PAS domain-containing protein 1 stabilizationHumans - Absorption
Following single and repeated doses, vadadustat is rapidly absorbed. The Tmax of vadadustat ranges between 2 and 3 hr. No significant accumulation was detected in healthy subjects given repeated doses of vadadustat. Compared to fasted conditions, the administration of a 450 mg vadadustat tablet with a standard high-fat meal decreased the Cmax and AUC by 27% and 6%, respectively. Vadadustat may be taken with or without food. The mean blood-to-plasma ratio of vadadustat went from 0.50 to 0.55, suggesting that the sequestration of vadadustat into red blood cells is minimal.6
- Volume of distribution
The apparent volume of distribution of vadadustat in patients with chronic kidney disease is 11.6 L.6
- Protein binding
The protein binding of vadadustat is greater than or equal to 99.5% in human plasma.6
- Metabolism
Vadadustat is mainly metabolized by UDP-glucuronosyltransferase (UGT) enzymes, forming O-glucuronide conjugates via direct glucuronidation. The metabolism of vadadustat via cytochrome P450s (CYPs) is minimal. The major metabolite of vadadustat is vadadustat-O-glucuronide, which has 15% of the AUC of plasma radioactivity, and it is catalyzed by multiple UGT enzymes, including UGT1A1, UGT1A7, UGT1A8 and UGT1A9. Vadadustat acyl glucuronide is a minor metabolite with 0.047% of the total radioactivity in plasma. None of the vadadustat metabolites are active.6
Hover over products below to view reaction partners
- Route of elimination
In healthy subjects given a single dose of 650 mg of radiolabelled vadadustat, 85.9% of the dose was recovered, with 58.9% appearing in urine and 26.9% in feces. Small amounts of the unchanged form of vadadustat are excreted in urine and feces (<1% and 9%, respectively).6
- Half-life
In patients with dialysis-dependent chronic kidney disease, the half-life of vadadustat was 9.2 hours.6
- Clearance
In healthy subjects given a single dose of 300 mg of vadadustat, the apparent total body clearance ranged from 1.7 L/h to 1.9 L/h.4 In patients with chronic kidney disease, the clearance of vadadustat is 0.8 L/h.8
- Adverse Effects
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An overdose of vadadustat may lead to extensions of the pharmacologic effects, such as increased hemoglobin levels and secondary polycythemia. In case of overdose, patients should be managed with clinically appropriate measures, such as dose reduction or treatment discontinuation. Patients should be carefully monitored and treated as clinically indicated. Approximately 16% of the vadadustat dose is removed by dialysis.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 software1,2-Benzodiazepine The serum concentration of 1,2-Benzodiazepine can be increased when it is combined with Vadadustat. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Vadadustat. Abiraterone The serum concentration of Abiraterone can be increased when it is combined with Vadadustat. Abrocitinib The metabolism of Abrocitinib can be decreased when combined with Vadadustat. Acalabrutinib The serum concentration of Acalabrutinib can be increased when it is combined with Vadadustat. - Food Interactions
- Take with or without food. The administration of a standard high-fat meal decreases the AUC of vadadustat by 6%, relative to fasted conditions; however, it may be administered 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.- International/Other Brands
- Vafseo (Akebia Therapeutics)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Vafseo Tablet, film coated 300 mg/1 Oral Akebia Therapeutics, Inc. 2024-03-28 Not applicable US 
Vafseo Tablet, film coated 450 mg Oral Medice Arzneimittel Pütter Gmb H & Co. Kg 2023-06-09 Not applicable EU 
Vafseo Tablet, film coated 150 mg Oral Medice Arzneimittel Pütter Gmb H & Co. Kg 2023-06-09 Not applicable EU Vafseo Tablet, film coated 150 mg/1 Oral Akebia Therapeutics, Inc. 2024-03-28 Not applicable US Vafseo Tablet, film coated 300 mg Oral Medice Arzneimittel Pütter Gmb H & Co. Kg 2023-06-09 Not applicable EU
Categories
- ATC Codes
- B03XA08 — Vadadustat
- Drug Categories
- Amino Acids
- Amino Acids, Peptides, and Proteins
- Antianemic Preparations
- BCRP/ABCG2 Inhibitors
- Blood and Blood Forming Organs
- Cytochrome P-450 CYP2B6 Inducers
- Cytochrome P-450 CYP2B6 Inducers (weak)
- Cytochrome P-450 CYP2C8 Inhibitors
- Cytochrome P-450 CYP2C8 Inhibitors (strength unknown)
- Cytochrome P-450 CYP2C9 Inhibitors
- Cytochrome P-450 CYP2C9 Inhibitors (strength unknown)
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 Enzyme Inhibitors
- Erythropoiesis-Stimulating Agents
- Hypoxia-Inducible Factor-Proline Dioxygenases, antagonists & inhibitors
- OAT3/SLC22A8 Inhibitors
- OAT3/SLC22A8 Substrates
- Pyridines
- UGT1A1 Inducers
- UGT1A1 Substrates
- UGT1A9 Substrates
- UGT2B7 substrates
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as n-acyl-alpha amino acids. These are compounds containing an alpha amino acid which bears an acyl group at its terminal nitrogen atom.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Carboxylic acids and derivatives
- Sub Class
- Amino acids, peptides, and analogues
- Direct Parent
- N-acyl-alpha amino acids
- Alternative Parents
- Phenylpyridines / Pyridinecarboxylic acids and derivatives / 2-heteroaryl carboxamides / Chlorobenzenes / Hydroxypyridines / Aryl chlorides / Vinylogous acids / Heteroaromatic compounds / Secondary carboxylic acid amides / Azacyclic compounds show 7 more
- Substituents
- 2-heteroaryl carboxamide / 3-phenylpyridine / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Carbonyl group / Carboxamide group / Carboxylic acid show 20 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- I60W9520VV
- CAS number
- 1000025-07-9
- InChI Key
- JGRXMPYUTJLTKT-UHFFFAOYSA-N
- InChI
- InChI=1S/C14H11ClN2O4/c15-10-3-1-2-8(4-10)9-5-11(18)13(16-6-9)14(21)17-7-12(19)20/h1-6,18H,7H2,(H,17,21)(H,19,20)
- IUPAC Name
- 2-{[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]formamido}acetic acid
- SMILES
- OC(=O)CNC(=O)C1=C(O)C=C(C=N1)C1=CC(Cl)=CC=C1
References
- Synthesis Reference
Shengde, W., et al. (2012). Prolyl hydroxylase inhibitors and methods of use (U.S. Patent No. US 8,323,671 B2). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/3d/62/ce/4a3024a944d334/US8323671.pdf
- General References
- Eckardt KU, Agarwal R, Aswad A, Awad A, Block GA, Bacci MR, Farag YMK, Fishbane S, Hubert H, Jardine A, Khawaja Z, Koury MJ, Maroni BJ, Matsushita K, McCullough PA, Lewis EF, Luo W, Parfrey PS, Pergola P, Sarnak MJ, Spinowitz B, Tumlin J, Vargo DL, Walters KA, Winkelmayer WC, Wittes J, Zwiech R, Chertow GM: Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis. N Engl J Med. 2021 Apr 29;384(17):1601-1612. doi: 10.1056/NEJMoa2025956. [Article]
- Nangaku M, Kondo K, Ueta K, Kokado Y, Kaneko G, Matsuda H, Kawaguchi Y, Komatsu Y: Efficacy and safety of vadadustat compared with darbepoetin alfa in Japanese anemic patients on hemodialysis: a Phase 3, multicenter, randomized, double-blind study. Nephrol Dial Transplant. 2021 Aug 27;36(9):1731-1741. doi: 10.1093/ndt/gfab055. [Article]
- Sanghani NS, Haase VH: Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience. Adv Chronic Kidney Dis. 2019 Jul;26(4):253-266. doi: 10.1053/j.ackd.2019.04.004. [Article]
- Paulson SK, Martinez J, Sawant R, Burke SK, Chavan A: Effect of Phosphate Binders and a Dietary Iron Supplement on the Pharmacokinetics of a Single Dose of Vadadustat in Healthy Adults. Clin Pharmacol Drug Dev. 2022 Apr;11(4):475-485. doi: 10.1002/cpdd.1033. Epub 2022 Feb 16. [Article]
- Akebia Therapeutics Press Release: Akebia Therapeutics Announces Top-Line Results from its PRO2TECT Global Phase 3 Program of Vadadustat for Treatment of Anemia Due to Chronic Kidney Disease in Adult Patients Not on Dialysis [Link]
- EMA Summary of Product Characteristics: Vafseo (vadadustat) film-coated tablets for oral use [Link]
- PR NewsWire: Akebia Receives European Commission Approval for Vafseo (vadadustat) for the Treatment of Symptomatic Anaemia Associated with Chronic Kidney Disease in Adults on Chronic Maintenance Dialysis [Link]
- EMA Assessment Report: Vafseo (vadadustat) film-coated tablets for oral use [Link]
- FDA Approved Drug Products: VAFSEO (vadadustat) tablets, for oral use [Link]
- Pharmaceutical Technology: Akebia’s Vafseo gains FDA approval for anaemia due to CKD [Link]
- External Links
- PubChem Compound
- 23634441
- PubChem Substance
- 347828530
- ChemSpider
- 34958379
- BindingDB
- 107704
- 2679296
- ChEMBL
- CHEMBL3646221
- ZINC
- ZINC000117532869
- PDBe Ligand
- A1Z
- Wikipedia
- Vadadustat
- PDB Entries
- 5opc / 5ox6 / 7ump
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 Completed Other Healthy Volunteers (HV) 1 somestatus stop reason just information to hide 3 Completed Treatment Anemia 1 somestatus stop reason just information to hide 3 Completed Treatment Anemia Associated With Chronic Kidney Disease (CKD) 1 somestatus stop reason just information to hide 3 Completed Treatment Anemia; Non-dialysis Dependent Chronic Kidney Disease 1 somestatus stop reason just information to hide 3 Completed Treatment Anemia; Peritoneal Dialysis Dependent Chronic Kidney Disease 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral 150 mg Tablet, film coated Oral 150 mg/1 Tablet, film coated Oral 300 mg Tablet, film coated Oral 300 mg/1 Tablet, film coated Oral 450 mg Tablet, film coated Oral 450 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8343952 No 2007-08-14 2027-08-14 US US7811595 No 2008-03-13 2028-03-13 US US11857543 No 2014-06-09 2034-06-09 US US11844756 No 2016-03-31 2036-03-31 US US11065237 No 2014-11-14 2034-11-14 US US9987262 No 2014-11-14 2034-11-14 US US8940773 No 2007-06-26 2027-06-26 US US8323671 No 2008-04-03 2028-04-03 US USRE47437 No 2007-06-26 2027-06-26 US US9701636 No 2014-11-14 2034-11-14 US US8598210 No 2007-06-26 2027-06-26 US US10149842 No 2014-11-14 2034-11-14 US US11324734 No 2016-03-31 2036-03-31 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility 0.041 mg/ml EMA Assessment Report - Predicted Properties
Property Value Source Water Solubility 0.0436 mg/mL ALOGPS logP 2.53 ALOGPS logP 2.2 Chemaxon logS -3.8 ALOGPS pKa (Strongest Acidic) 3.12 Chemaxon pKa (Strongest Basic) 1.15 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 99.52 Å2 Chemaxon Rotatable Bond Count 4 Chemaxon Refractivity 75.51 m3·mol-1 Chemaxon Polarizability 29.63 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS splash10-001i-1090000000-9f4910edaee2dfdf5001 Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-053r-0094000000-9c949bb7487015af18ef Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-001i-1090000000-8349e4af5f5b1996e797 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0f89-2090000000-9f579bf31d19cff684f1 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0535-1490000000-a0a72af2c0ce41066f5b Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-001i-9040000000-d53f8ee03acfaad6d189 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-001i-9410000000-4d26f266695f6a4764ce Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 161.76668 predictedDeepCCS 1.0 (2019) [M+H]+ 164.12468 predictedDeepCCS 1.0 (2019) [M+Na]+ 170.22792 predictedDeepCCS 1.0 (2019)
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
- Inhibitor
- General Function
- Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF1B. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN1 is the most important isozyme under normoxia and, through regulating the stability of HIF1, involved in various hypoxia-influenced processes such as angiogenesis in retinal and cardiac functionality. Target proteins are preferentially recognized via a LXXLAP motif.
- Specific Function
- 2-oxoglutarate-dependent dioxygenase activity
- Gene Name
- EGLN1
- Uniprot ID
- Q9GZT9
- Uniprot Name
- Egl nine homolog 1
- Molecular Weight
- 46020.585 Da
References
- Sanghani NS, Haase VH: Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience. Adv Chronic Kidney Dis. 2019 Jul;26(4):253-266. doi: 10.1053/j.ackd.2019.04.004. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Prolyl hydroxylase that mediates hydroxylation of proline residues in target proteins, such as ATF4, IKBKB, CEP192 and HIF1A (PubMed:11595184, PubMed:12039559, PubMed:15925519, PubMed:16509823, PubMed:17114296, PubMed:23932902). Target proteins are preferentially recognized via a LXXLAP motif (PubMed:11595184, PubMed:12039559, PubMed:15925519). Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins (PubMed:11595184, PubMed:12039559, PubMed:12181324, PubMed:15925519, PubMed:19339211). Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A (PubMed:11595184, PubMed:12039559, PubMed:12181324, PubMed:15925519). Also hydroxylates HIF2A (PubMed:11595184, PubMed:12039559, PubMed:15925519). Has a preference for the CODD site for both HIF1A and HIF2A (PubMed:11595184, PubMed:12039559, PubMed:15925519). Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex (PubMed:11595184, PubMed:12039559, PubMed:15925519). Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes (PubMed:11595184, PubMed:12039559, PubMed:15925519). EGLN2 is involved in regulating hypoxia tolerance and apoptosis in cardiac and skeletal muscle (PubMed:11595184, PubMed:12039559, PubMed:15925519). Also regulates susceptibility to normoxic oxidative neuronal death (PubMed:11595184, PubMed:12039559, PubMed:15925519). Links oxygen sensing to cell cycle and primary cilia formation by hydroxylating the critical centrosome component CEP192 which promotes its ubiquitination and subsequent proteasomal degradation (PubMed:23932902). Hydroxylates IKBKB, mediating NF-kappa-B activation in hypoxic conditions (PubMed:17114296). Also mediates hydroxylation of ATF4, leading to decreased protein stability of ATF4 (By similarity).
- Specific Function
- 2-oxoglutarate-dependent dioxygenase activity
- Gene Name
- EGLN2
- Uniprot ID
- Q96KS0
- Uniprot Name
- Prolyl hydroxylase EGLN2
- Molecular Weight
- 43650.03 Da
References
- Sanghani NS, Haase VH: Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience. Adv Chronic Kidney Dis. 2019 Jul;26(4):253-266. doi: 10.1053/j.ackd.2019.04.004. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Prolyl hydroxylase that mediates hydroxylation of proline residues in target proteins, such as PKM, TELO2, ATF4 and HIF1A (PubMed:19584355, PubMed:20978507, PubMed:21483450, PubMed:21575608, PubMed:21620138, PubMed:22797300). Target proteins are preferentially recognized via a LXXLAP motif. Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins (PubMed:11595184, PubMed:12181324). Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A (PubMed:11595184, PubMed:12181324). Also hydroxylates HIF2A (PubMed:11595184, PubMed:12181324). Has a preference for the CODD site for both HIF1A and HIF2A (PubMed:11595184, PubMed:12181324). Hydroxylation on the NODD site by EGLN3 appears to require prior hydroxylation on the CODD site (PubMed:11595184, PubMed:12181324). Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex (PubMed:11595184, PubMed:12181324). Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes (PubMed:11595184, PubMed:12181324). ELGN3 is the most important isozyme in limiting physiological activation of HIFs (particularly HIF2A) in hypoxia. Also hydroxylates PKM in hypoxia, limiting glycolysis (PubMed:21483450, PubMed:21620138). Under normoxia, hydroxylates and regulates the stability of ADRB2 (PubMed:19584355). Regulator of cardiomyocyte and neuronal apoptosis. In cardiomyocytes, inhibits the anti-apoptotic effect of BCL2 by disrupting the BAX-BCL2 complex (PubMed:20849813). In neurons, has a NGF-induced proapoptotic effect, probably through regulating CASP3 activity (PubMed:16098468). Also essential for hypoxic regulation of neutrophilic inflammation (PubMed:21317538). Plays a crucial role in DNA damage response (DDR) by hydroxylating TELO2, promoting its interaction with ATR which is required for activation of the ATR/CHK1/p53 pathway (PubMed:22797300). Also mediates hydroxylation of ATF4, leading to decreased protein stability of ATF4 (Probable).
- Specific Function
- 2-oxoglutarate-dependent dioxygenase activity
- Gene Name
- EGLN3
- Uniprot ID
- Q9H6Z9
- Uniprot Name
- Prolyl hydroxylase EGLN3
- Molecular Weight
- 27261.06 Da
References
- Sanghani NS, Haase VH: Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience. Adv Chronic Kidney Dis. 2019 Jul;26(4):253-266. doi: 10.1053/j.ackd.2019.04.004. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Stabilization
- General Function
- Functions as a master transcriptional regulator of the adaptive response to hypoxia (PubMed:11292861, PubMed:11566883, PubMed:15465032, PubMed:16973622, PubMed:17610843, PubMed:18658046, PubMed:20624928, PubMed:22009797, PubMed:30125331, PubMed:9887100). Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, HILPDA, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia (PubMed:11292861, PubMed:11566883, PubMed:15465032, PubMed:16973622, PubMed:17610843, PubMed:20624928, PubMed:22009797, PubMed:30125331, PubMed:9887100). Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease (PubMed:22009797). Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity). Activation requires recruitment of transcriptional coactivators such as CREBBP and EP300 (PubMed:16543236, PubMed:9887100). Activity is enhanced by interaction with NCOA1 and/or NCOA2 (PubMed:10594042). Interaction with redox regulatory protein APEX1 seems to activate CTAD and potentiates activation by NCOA1 and CREBBP (PubMed:10202154, PubMed:10594042). Involved in the axonal distribution and transport of mitochondria in neurons during hypoxia (PubMed:19528298).
- Specific Function
- cis-regulatory region sequence-specific DNA binding
- Gene Name
- HIF1A
- Uniprot ID
- Q16665
- Uniprot Name
- Hypoxia-inducible factor 1-alpha
- Molecular Weight
- 92669.595 Da
References
- Sanghani NS, Haase VH: Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience. Adv Chronic Kidney Dis. 2019 Jul;26(4):253-266. doi: 10.1053/j.ackd.2019.04.004. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Stabilization
- General Function
- Transcription factor involved in the induction of oxygen regulated genes. Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity). Regulates the vascular endothelial growth factor (VEGF) expression and seems to be implicated in the development of blood vessels and the tubular system of lung. May also play a role in the formation of the endothelium that gives rise to the blood brain barrier. Potent activator of the Tie-2 tyrosine kinase expression. Activation requires recruitment of transcriptional coactivators such as CREBBP and probably EP300. Interaction with redox regulatory protein APEX1 seems to activate CTAD (By similarity).
- Specific Function
- DNA-binding transcription activator activity, RNA polymerase II-specific
- Gene Name
- EPAS1
- Uniprot ID
- Q99814
- Uniprot Name
- Endothelial PAS domain-containing protein 1
- Molecular Weight
- 96458.235 Da
References
- Sanghani NS, Haase VH: Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience. Adv Chronic Kidney Dis. 2019 Jul;26(4):253-266. doi: 10.1053/j.ackd.2019.04.004. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInducer
- General Function
- Isoform 1 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:12181437, PubMed:15472229, PubMed:18004206, PubMed:18004212, PubMed:18719240, PubMed:19830808, PubMed:23288867). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004206, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol, estrone and estriol (PubMed:15472229, PubMed:18719240, PubMed:23288867). Involved in the glucuronidation of bilirubin, a degradation product occurring in the normal catabolic pathway that breaks down heme in vertebrates (PubMed:17187418, PubMed:18004206, PubMed:19830808, PubMed:24525562). Also catalyzes the glucuronidation the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist losartan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:18004212, PubMed:20610558).
- Specific Function
- enzyme binding
- Gene Name
- UGT1A1
- Uniprot ID
- P22309
- Uniprot Name
- UDP-glucuronosyltransferase 1A1
- Molecular Weight
- 59590.91 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Isoform 1 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:12181437, PubMed:15470161, PubMed:18004212, PubMed:18052087, PubMed:18674515, PubMed:18719240, PubMed:20610558, PubMed:23360619). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormone epiestradiol (PubMed:18719240). Also catalyzes the glucuronidation of the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist caderastan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:18004212, PubMed:20610558, PubMed:23360619). Also metabolizes mycophenolate, an immunosuppressive agent (PubMed:15470161).
- Specific Function
- enzyme binding
- Gene Name
- UGT1A7
- Uniprot ID
- Q9HAW7
- Uniprot Name
- UDP-glucuronosyltransferase 1A7
- Molecular Weight
- 59818.315 Da
References
- EMA Summary of Product Characteristics: Vafseo (vadadustat) film-coated tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Isoform 1 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:16595710, PubMed:18004212, PubMed:18052087, PubMed:18674515, PubMed:18719240, PubMed:19545173, PubMed:23288867). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:15472229, PubMed:16595710, PubMed:23288867). Catalyzes the glucuronidation of endogenous steroid hormones such as androgens and estrogens (PubMed:15472229, PubMed:16595710, PubMed:18719240, PubMed:23288867). Produces dihydrotestosterone (DHT) diglucuronide from the DHT after two subsequent glucoronidation steps (PubMed:16595710). Also catalyzes the glucuronidation of the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist caderastan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Also metabolizes mycophenolate, an immunosuppressive agent (PubMed:15470161, PubMed:18004212).
- Specific Function
- enzyme binding
- Gene Name
- UGT1A8
- Uniprot ID
- Q9HAW9
- Uniprot Name
- UDP-glucuronosyltransferase 1A8
- Molecular Weight
- 59741.035 Da
References
- EMA Summary of Product Characteristics: Vafseo (vadadustat) film-coated tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Isoform 1 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:12181437, PubMed:15470161, PubMed:15472229, PubMed:18004212, PubMed:18052087, PubMed:18674515, PubMed:19545173). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol and estrone (PubMed:15472229). Also catalyzes the glucuronidation of the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist caderastan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:20610558). Also metabolizes mycophenolate, an immunosuppressive agent (PubMed:15470161, PubMed:18004212).
- Specific Function
- enzyme binding
- Gene Name
- UGT1A9
- Uniprot ID
- O60656
- Uniprot Name
- UDP-glucuronosyltransferase 1A9
- Molecular Weight
- 59940.495 Da
References
- EMA Summary of Product Characteristics: Vafseo (vadadustat) film-coated 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: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
- 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
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- 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
- Pharmaceuticals and Medical Devices Agency: Report on the Deliberation Results for Vadadustat [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Downregulator
- 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
- EMA Summary of Product Characteristics: Vafseo (vadadustat) film-coated tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- 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
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
- EMA Assessment Report: Vafseo (vadadustat) film-coated tablets for oral use [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- 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
- EMA Summary of Product Characteristics: Vafseo (vadadustat) film-coated tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- 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
- EMA Summary of Product Characteristics: Vafseo (vadadustat) film-coated tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Secondary active transporter that functions as a Na(+)-independent organic anion (OA)/dicarboxylate antiporter where the uptake of one molecule of OA into the cell is coupled with an efflux of one molecule of intracellular dicarboxylate such as 2-oxoglutarate or glutarate (PubMed:11669456, PubMed:11907186, PubMed:14675047, PubMed:22108572, PubMed:23832370, PubMed:28534121, PubMed:9950961). Mediates the uptake of OA across the basolateral side of proximal tubule epithelial cells, thereby contributing to the renal elimination of endogenous OA from the systemic circulation into the urine (PubMed:9887087). 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). Transports prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may contribute to their renal excretion (PubMed:11907186). Also mediates the uptake of cyclic nucleotides such as cAMP and cGMP (PubMed:26377792). Involved in the transport of neuroactive tryptophan metabolites kynurenate (KYNA) and xanthurenate (XA) and may contribute to their secretion from the brain (PubMed:22108572, PubMed:23832370). May transport glutamate (PubMed:26377792). Also involved in the disposition of uremic toxins and potentially toxic xenobiotics by the renal organic anion secretory pathway, helping reduce their undesired toxicological effects on the body (PubMed:11669456, PubMed:14675047). Uremic toxins include the indoxyl sulfate (IS), hippurate/N-benzoylglycine (HA), indole acetate (IA), 3-carboxy-4- methyl-5-propyl-2-furanpropionate (CMPF) and urate (PubMed:14675047, PubMed:26377792). Xenobiotics include the mycotoxin ochratoxin (OTA) (PubMed:11669456). May also contribute to the transport of organic compounds in testes across the blood-testis-barrier (PubMed:35307651).
- Specific Function
- alpha-ketoglutarate transmembrane transporter activity
- Gene Name
- SLC22A6
- Uniprot ID
- Q4U2R8
- Uniprot Name
- Solute carrier family 22 member 6
- Molecular Weight
- 61815.78 Da
References
- EMA Summary of Product Characteristics: Vafseo (vadadustat) film-coated tablets for oral use [Link]
Drug created at October 20, 2016 21:44 / Updated at April 03, 2024 01:15