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Identification
- Summary
Febuxostat is a xanthine oxidase inhibitor used for the management of chronic hyperuricemia in adults with gout who have an inadequate response or intolerance to allopurinol.
- Brand Names
- Adenuric, Uloric
- Generic Name
- Febuxostat
- DrugBank Accession Number
- DB04854
- Background
Febuxostat is a non-purine xanthine oxidase (XO) inhibitor.4 In early 2008, febuxostat was granted marketing authorization by the European Commission for the treatment of chronic hyperuricemia and gout.5 In the following year, the FDA for approved febuxostat for use in the chronic management of hyperuricemia in adult patients with gout who have an inadequate response or intolerance to allopurinol.10 Gout is a form of arthritis that is caused by the accumulation of uric acid crystal in or around a joint, leading to inflammation and further deposition of uric acid crystal deposition in bones, joints, tissues, and other organs in the long term. Gout is closely associated with hyperuricemia. Febuxostat works by inhibiting the activity of an enzyme that is responsible for the synthesis of uric acid, thereby reducing serum uric acid levels.5
In February 2019, a black box warning for febuxostat was added, based on the findings of a post-market clinical study (the CARES trial) where there was an increased risk of cardiovascular (CV) fatal outcomes in patients with gout and known cardiovascular disease treated with febuxostat, when compared to those treated with allopurinol. The manufacturer and the FDA advise health professionals to limit the use of febuxostat to second-line therapy in patients who have inadequate response or intolerance to allopurinol, and to avoid the use of febuxostat in patients with cardiovascular diseases.1,9
- Type
- Small Molecule
- Groups
- Approved
- Structure
Structure for Febuxostat (DB04854)
- Weight
- Average: 316.375
Monoisotopic: 316.088163078 - Chemical Formula
- C16H16N2O3S
- Synonyms
- 2-(3-cyano-4-isobutoxyphenyl)-4-methyl- 1,3-thiazole-5-carboxylic acid
- Fébuxostat
- Febuxostat
- Febuxostatum
- External IDs
- TEI-6720
- TMX-67
Pharmacology
- Indication
Febuxostat is indicated for the chronic management of hyperuricemia in adult patients with gout who have an inadequate response to a maximally titrated dose of allopurinol, who are intolerant to allopurinol, or for whom treatment with allopurinol is not advisable.13 It is not recommended for the treatment of asymptomatic hyperuricemia 10 or secondary hyperuricemia.7
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Management of Chronic, symptomatic hyperuricemia •••••••••••• ••••• •••••••••• •••••••• •• •• •••••••••• •• ••••••••••• •••••• - Contraindications & Blackbox Warnings
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Febuxostat is a novel, selective xanthine oxidase/dehydrogenase inhibitor that works by decreasing serum uric acid in a dose-dependent manner. In healthy subjects, febuxostat decreased the mean serum uric acid and serum xanthine concentrations, as well as the total urinary uric acid excretion. Febuxostat at daily doses of 40-80 mg reduced the 24-hour mean serum uric acid concentrations by 40 to 55%.10 Closely related to the drug-induced reduction of serum uric acid levels and mobilization of urate crystals in tissue deposits, febuxostat is associated with gout flares.7
Unlike allopurinol and oxypurinol, febuxostat has no inhibitory actions against other enzymes involved in purine and pyrimidine synthesis and metabolism, because it does not structurally resemble purines or pyrimidines.5
- Mechanism of action
Gout is a form of acute arthritis that is characterized by the accumulation of crystals of monosodium urate and urate crystals in or around a joint, leading to inflammation and persistent urate crystal deposition in bones, joints, tissues, and other organs that may exacerbate over time. Hyperuricemia is closely related to gout, whereby it may exist for many years before the first clinical attack of gout; thus, aberrated serum uric acid levels and hyperuricemia are believed to be the biochemical aberration involved in the pathogenesis of gout.5 Xanthine oxidoreductase (XOR) can act as a xanthine oxidase or xanthine dehydrogenase. In humans, it is a critical enzyme for uric acid production as it catalyzes the oxidation reaction steps from hypoxanthine to xanthine and from xanthine to uric acid in the pathway of purine metabolism.6 Febuxostat potently inhibits XOR, blocking both its oxidase and dehydrogenase activities. With high affinity, febuxostat binds to XOR in a molecular channel leading to the molybdenum-pterin active site, where allopurinol demonstrates relatively weak competitive inhibition.5
XOR is mainly found in the dehydrogenase form under normal physiological conditions; however, in inflammatory conditions, XOR can be converted into the xanthine oxidase form, which catalyzes reactions that produce reactive oxygen species (ROS), such as peroxynitrite. ROS contribute to vascular inflammation and alterations in vascular function. As febuxostat can inhibit both forms of XOR, it can inhibit ROS formation, oxidative stress, and inflammation.2 In a rat model, febuxostat suppressed renal ischemia-reperfusion injury by attenuating oxidative stress.3
Target Actions Organism AXanthine dehydrogenase/oxidase inhibitorHumans - Absorption
After oral administration, about 85% of febuxostat is absorbed rapidly.5 Tmax ranges from 1 to 1.5 hours. Following once-daily oral administration, Cmax was approximately 1.6 ± 0.6 mcg/mL at a dose of 40 mg febuxostat and 2.6 ± 1.7 mcg/mL at a dose of 80 mg febuxostat.10
A high-fat meal decreased Cmax by 49% and AUC by 18%, but there were no clinically significant changes in the ability of febuxostat to decrease serum uric acid concentrations.10
- Volume of distribution
The apparent steady-state volume of distribution (Vss/F) of febuxostat ranges from 29 to 75 L, indicating a low to medium volume of distribution.8
- Protein binding
Febuxostat is approximately 99.2% bound to plasma proteins, primarily to albumin. Plasma protein binding is constant over the concentration range achieved with 40 mg and 80 mg doses.10
- Metabolism
Febuxostat is metabolized in the liver by UDP-glucuronosyltransferase (UGT) and Cytochrome P450 (CYP) enzymes, with the relative contribution of each enzyme isoform in the metabolism of febuxostat not fully elucidated. UGT1A1, UGT1A3, UGT1A9, and UGT2B7 mediate conjugation of febuxostat,10 which approximately accounts for 22–44% of the metabolism of the total dose administered, to produce the acyl-glucuronide metabolite.5 CYP1A2, CYP2C8, CYP2C9, and non-P450 enzymes are responsible for the oxidation reaction, which accounts for 2-8% of the metabolism of the dose.5 Oxidation reaction produces 67M-1, 67M-2, and 67M-4, which are pharmacologically active metabolites. 67M-1, 67M-2, and 67M-4 can further undergo glucuronidation and sulfation.8 Hydroxy metabolites are present in human plasma at much lower concentrations than the parent drug.10
Hover over products below to view reaction partners
- Route of elimination
Febuxostat is eliminated via both hepatic and renal pathways. Following oral administration of 80 mg radiolabeled febuxostat, approximately 49% of the dose was recovered in the urine. In urine, about 3% of the recovered dose accounted for unchanged febuxostat, 30% accounted for the acyl glucuronide metabolite, 13% accounted for oxidative metabolites and their conjugates, and 3% accounted for unidentified metabolites.10
Approximately 45% of the total dose was recovered in the feces, where 12% of the dose accounted for the unchanged parent drug. About 1% accounted for the acyl glucuronide metabolite, 25% accounted for oxidative metabolites and their conjugates, and 7% accounted for unidentified metabolites.10
- Half-life
The apparent mean terminal elimination half-life of approximately 5 to 8 hours.10
- Clearance
Following oral administration of single doses of 10 to 240 mg, the mean apparent total clearance ranged from 10 to 12 L/h.5
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Oral lowest published toxic dose (TDLO) in humans is 1.82 mg/kg/14D (intermittent).9 Oral LD50 is 300 mg/kg in mice, 3200 mg/kg in rabbits, and 980 mg/kg in rats.12
No dose-limiting toxicities were observed with febuxostat administered at doses up to 300 mg daily for seven days in healthy subjects. There are no reports of overdose of febuxostat in clinical studies and there is no known antidote. Overdose should be managed by symptomatic and supportive care.10
- 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 excretion of Abemaciclib can be decreased when combined with Febuxostat. Adenine The metabolism of Febuxostat can be decreased when combined with Adenine. Afatinib The excretion of Afatinib can be decreased when combined with Febuxostat. Allopurinol The excretion of Allopurinol can be decreased when combined with Febuxostat. Alpelisib The serum concentration of Alpelisib can be increased when it is combined with Febuxostat. - Food Interactions
- Take with or without food. A high fat meal decreases Cmax and AUC in a clinically insignificant way.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Febuxostat hemihydrate 7KC4X53ED3 442664-09-7 PBDGWWSMDHCTAJ-UHFFFAOYSA-N - Product Images
- International/Other Brands
- Atenurix (Ajanta Pharma Phil) / Barif (Square) / Feburic (Teijin Pharma)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Adenuric Tablet, film coated 80 mg Oral Menarini International Operations Luxembourg S.A. 2016-09-07 Not applicable EU 
Adenuric Tablet, film coated 120 mg Oral Menarini International Operations Luxembourg S.A. 2016-09-07 Not applicable EU Adenuric Tablet, film coated 120 mg Oral Menarini International Operations Luxembourg S.A. 2016-09-07 Not applicable EU Adenuric Tablet, film coated 120 mg Oral Menarini International Operations Luxembourg S.A. 2016-09-07 Not applicable EU Adenuric Tablet, film coated 120 mg Oral Menarini International Operations Luxembourg S.A. 2016-09-07 Not applicable EU - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Auro-febuxostat Tablet 80 mg Oral Auro Pharma Inc 2023-05-15 Not applicable Canada 
Febuxostat Tablet, film coated 80 mg/1 Oral Indoco Remedies Limited 2017-02-15 Not applicable US 
Febuxostat Tablet, film coated 40 mg/1 Oral American Health Packaging 2021-09-02 Not applicable US Febuxostat Tablet, film coated 40 mg/1 Oral Major Pharmaceuticals 2024-05-22 Not applicable US Febuxostat Tablet 40 mg/1 Oral Golden State Medical Supply, Inc. 2019-10-15 Not applicable US
Categories
- ATC Codes
- M04AA03 — Febuxostat
- Drug Categories
- Antigout Preparations
- Antirheumatic Agents
- BCRP/ABCG2 Inhibitors
- Cytochrome P-450 CYP1A2 Substrates
- Cytochrome P-450 CYP2C8 Substrates
- Cytochrome P-450 CYP2C9 Substrates
- Cytochrome P-450 Substrates
- Drugs causing inadvertant photosensitivity
- Musculo-Skeletal System
- Photosensitizing Agents
- Preparations Inhibiting Uric Acid Production
- Sulfur Compounds
- Thiazoles
- UGT1A1 Substrates
- UGT1A3 substrates
- UGT1A9 Substrates
- UGT2B7 substrates
- Xanthine Oxidase Inhibitors
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as thiazolecarboxylic acids and derivatives. These are heterocyclic compounds containing a thiazole ring which bears a carboxylic acid group (or a derivative thereof).
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Azoles
- Sub Class
- Thiazoles
- Direct Parent
- Thiazolecarboxylic acids and derivatives
- Alternative Parents
- Phenoxy compounds / Phenol ethers / Benzonitriles / 2,4,5-trisubstituted thiazoles / Alkyl aryl ethers / Heteroaromatic compounds / Nitriles / Monocarboxylic acids and derivatives / Carboxylic acids / Azacyclic compounds show 3 more
- Substituents
- 2,4,5-trisubstituted 1,3-thiazole / Alkyl aryl ether / Aromatic heteromonocyclic compound / Azacycle / Benzenoid / Benzonitrile / Carbonitrile / Carboxylic acid / Carboxylic acid derivative / Ether show 14 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- nitrile, 1,3-thiazolemonocarboxylic acid (CHEBI:45943)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 101V0R1N2E
- CAS number
- 144060-53-7
- InChI Key
- BQSJTQLCZDPROO-UHFFFAOYSA-N
- InChI
- InChI=1S/C16H16N2O3S/c1-9(2)8-21-13-5-4-11(6-12(13)7-17)15-18-10(3)14(22-15)16(19)20/h4-6,9H,8H2,1-3H3,(H,19,20)
- IUPAC Name
- 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid
- SMILES
- CC(C)COC1=C(C=C(C=C1)C1=NC(C)=C(S1)C(O)=O)C#N
References
- Synthesis Reference
- General References
- Gandhi PK, Gentry WM, Bottorff MB: Cardiovascular thromboembolic events associated with febuxostat: investigation of cases from the FDA adverse event reporting system database. Semin Arthritis Rheum. 2013 Jun;42(6):562-6. doi: 10.1016/j.semarthrit.2012.11.002. Epub 2013 Jan 24. [Article]
- Saban-Ruiz J, Alonso-Pacho A, Fabregate-Fuente M, de la Puerta Gonzalez-Quevedo C: Xanthine oxidase inhibitor febuxostat as a novel agent postulated to act against vascular inflammation. Antiinflamm Antiallergy Agents Med Chem. 2013;12(1):94-9. [Article]
- Tsuda H, Kawada N, Kaimori JY, Kitamura H, Moriyama T, Rakugi H, Takahara S, Isaka Y: Febuxostat suppressed renal ischemia-reperfusion injury via reduced oxidative stress. Biochem Biophys Res Commun. 2012 Oct 19;427(2):266-72. doi: 10.1016/j.bbrc.2012.09.032. Epub 2012 Sep 17. [Article]
- Edwards NL: Febuxostat: a new treatment for hyperuricaemia in gout. Rheumatology (Oxford). 2009 May;48 Suppl 2:ii15-ii19. doi: 10.1093/rheumatology/kep088. [Article]
- Hu M, Tomlinson B: Febuxostat in the management of hyperuricemia and chronic gout: a review. Ther Clin Risk Manag. 2008 Dec;4(6):1209-20. doi: 10.2147/tcrm.s3310. [Article]
- Nishino T, Okamoto K: Mechanistic insights into xanthine oxidoreductase from development studies of candidate drugs to treat hyperuricemia and gout. J Biol Inorg Chem. 2015 Mar;20(2):195-207. doi: 10.1007/s00775-014-1210-x. Epub 2014 Dec 12. [Article]
- Gerriets V, Jialal I: Febuxostat . [Article]
- Grabowski BA, Khosravan R, Vernillet L, Mulford DJ: Metabolism and excretion of [14C] febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase, in healthy male subjects. J Clin Pharmacol. 2011 Feb;51(2):189-201. doi: 10.1177/0091270010365549. Epub 2010 Mar 30. [Article]
- Takeda: Important Safety Information on ULORIC (febuxostat) – Increased Risk of Cardiovascular Fatal Outcomes [Link]
- FDA Approved Products: ULORIC (febuxostat) tablets, for oral use (February 2019) [Link]
- Selleck Chemicals: Febuxostat Safety Data Sheet [Link]
- Clearsynth Labs: Febuxostat D9 Safety Data Sheet [Link]
- FDA Approved Drug Products: ULORIC (febuxostat) tablets, for oral use (April 2023) [Link]
- External Links
- Human Metabolome Database
- HMDB0252185
- KEGG Drug
- D01206
- PubChem Compound
- 134018
- PubChem Substance
- 310264854
- ChemSpider
- 118173
- BindingDB
- 50320491
- 73689
- ChEBI
- 31596
- ChEMBL
- CHEMBL1164729
- ZINC
- ZINC000000005423
- PharmGKB
- PA165958521
- PDBe Ligand
- TEI
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- PDRhealth
- PDRhealth Drug Page
- Wikipedia
- Febuxostat
- PDB Entries
- 1n5x / 7er9
- FDA label
- Download (115 KB)
- MSDS
- Download (568 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Completed Basic Science Cardiovascular System / Flow-mediated Vasodilatation (FMD) / Hypertension / Stress Oxidative 1 somestatus stop reason just information to hide Not Available Completed Prevention Chronic Kidney Disease, Stage 3 (Moderate) / Prophylaxis of Contrast-induced nephropathy 1 somestatus stop reason just information to hide Not Available Completed Treatment Abnormal Renal Function / Chronic Kidney Disease (CKD) / Hyperuricemia 1 somestatus stop reason just information to hide Not Available Completed Treatment Chronic Kidney Disease (CKD) / Diabetes 1 somestatus stop reason just information to hide Not Available Completed Treatment Complication of Hemodialysis / Hyperuricemia 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, coated Oral 40 mg Tablet, film coated Oral 80.00 mg Tablet, film coated Oral Film Oral 40 mg/1 Film Oral 80 mg/1 Tablet, coated Oral 40 mg/1 Tablet, coated Oral 80 mg/1 Tablet, film coated Oral 40 mg/1 Tablet, film coated Oral 80 mg/1 Tablet, coated Oral 120 MG Tablet, film coated Oral 120 MG Tablet, film coated Oral 40 MG Capsule, liquid filled Oral 120 mg Capsule, liquid filled Oral 40 mg Capsule, liquid filled Oral 80 mg Tablet Oral 40 mg Tablet Oral 80.000 mg Tablet Oral 40 mg/1 Tablet Oral 80 mg/1 Tablet Oral 80 mg Tablet, coated Oral 80 mg Tablet, film coated Oral 80 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US5614520 No 1997-03-25 2019-03-25 US US8372872 No 2013-02-12 2031-09-08 US US9107912 No 2015-08-18 2031-09-08 US US6225474 No 2001-05-01 2019-06-18 US US7361676 No 2008-04-22 2024-03-08 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 238-239° Patent WO2012056442 A1 water solubility <1 mg/mL Selleck Chemicals Safety Data Sheet - Predicted Properties
Property Value Source Water Solubility 0.0183 mg/mL ALOGPS logP 3.8 ALOGPS logP 3.52 Chemaxon logS -4.2 ALOGPS pKa (Strongest Acidic) 3.08 Chemaxon pKa (Strongest Basic) 0.39 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 83.21 Å2 Chemaxon Rotatable Bond Count 5 Chemaxon Refractivity 93.93 m3·mol-1 Chemaxon Polarizability 33.88 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9865 Blood Brain Barrier + 0.7853 Caco-2 permeable + 0.5126 P-glycoprotein substrate Non-substrate 0.7834 P-glycoprotein inhibitor I Non-inhibitor 0.8351 P-glycoprotein inhibitor II Non-inhibitor 0.8076 Renal organic cation transporter Non-inhibitor 0.8845 CYP450 2C9 substrate Non-substrate 0.7229 CYP450 2D6 substrate Non-substrate 0.8064 CYP450 3A4 substrate Non-substrate 0.5899 CYP450 1A2 substrate Inhibitor 0.7936 CYP450 2C9 inhibitor Inhibitor 0.6712 CYP450 2D6 inhibitor Non-inhibitor 0.8662 CYP450 2C19 inhibitor Inhibitor 0.734 CYP450 3A4 inhibitor Non-inhibitor 0.7441 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.6509 Ames test Non AMES toxic 0.7486 Carcinogenicity Non-carcinogens 0.8601 Biodegradation Not ready biodegradable 0.9401 Rat acute toxicity 2.3811 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9964 hERG inhibition (predictor II) Non-inhibitor 0.9192
Spectra
- Mass Spec (NIST)
- Download (42.2 KB)
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 191.2577587 predictedDarkChem Lite v0.1.0 [M-H]- 191.4984587 predictedDarkChem Lite v0.1.0 [M-H]- 175.15535 predictedDeepCCS 1.0 (2019) [M+H]+ 191.8784587 predictedDarkChem Lite v0.1.0 [M+H]+ 192.0826587 predictedDarkChem Lite v0.1.0 [M+H]+ 177.51337 predictedDeepCCS 1.0 (2019) [M+Na]+ 191.9084587 predictedDarkChem Lite v0.1.0 [M+Na]+ 184.5985 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
- Key enzyme in purine degradation. Catalyzes the oxidation of hypoxanthine to xanthine. Catalyzes the oxidation of xanthine to uric acid. Contributes to the generation of reactive oxygen species. Has also low oxidase activity towards aldehydes (in vitro)
- Specific Function
- 2 iron, 2 sulfur cluster binding
- Gene Name
- XDH
- Uniprot ID
- P47989
- Uniprot Name
- Xanthine dehydrogenase/oxidase
- Molecular Weight
- 146422.99 Da
References
- Saban-Ruiz J, Alonso-Pacho A, Fabregate-Fuente M, de la Puerta Gonzalez-Quevedo C: Xanthine oxidase inhibitor febuxostat as a novel agent postulated to act against vascular inflammation. Antiinflamm Antiallergy Agents Med Chem. 2013;12(1):94-9. [Article]
- Nishino T, Okamoto K: Mechanistic insights into xanthine oxidoreductase from development studies of candidate drugs to treat hyperuricemia and gout. J Biol Inorg Chem. 2015 Mar;20(2):195-207. doi: 10.1007/s00775-014-1210-x. Epub 2014 Dec 12. [Article]
- Pohar S, Murphy G: Febuxostat for prevention of gout attacks. Issues Emerg Health Technol. 2006 Aug;(87):1-4. [Article]
- Hu M, Tomlinson B: Febuxostat in the management of hyperuricemia and chronic gout: a review. Ther Clin Risk Manag. 2008 Dec;4(6):1209-20. doi: 10.2147/tcrm.s3310. [Article]
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- FDA Approved Products: ULORIC (febuxostat) tablets, for oral use (February 2019) [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- 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: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
- FDA Approved Products: ULORIC (febuxostat) tablets, for oral use (February 2019) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- 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: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 Products: ULORIC (febuxostat) tablets, for oral use (February 2019) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- 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: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
- FDA Approved Products: ULORIC (febuxostat) tablets, for oral use (February 2019) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- 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
- FDA Approved Products: ULORIC (febuxostat) tablets, for oral use (February 2019) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:11555828, PubMed:12865317). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2 (PubMed:11555828, PubMed:12865317). Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). May act as a major enzyme for all-trans retinoic acid biosynthesis in the liver. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer (PubMed:19965576). Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA (PubMed:9435160). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin (PubMed:14725854). Metabolizes caffeine via N3-demethylation (Probable)
- Specific Function
- aromatase activity
- Gene Name
- CYP1A2
- Uniprot ID
- P05177
- Uniprot Name
- Cytochrome P450 1A2
- Molecular Weight
- 58406.915 Da
References
- FDA Approved Products: ULORIC (febuxostat) tablets, for oral use (February 2019) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:15766564, PubMed:19965576, PubMed:7574697). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316)
- Specific Function
- arachidonic acid epoxygenase activity
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- FDA Approved Products: ULORIC (febuxostat) tablets, for oral use (February 2019) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:15766564, PubMed:19965576, PubMed:7574697, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9435160, PubMed:9866708). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031)
- Specific Function
- (R)-limonene 6-monooxygenase activity
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- FDA Approved Products: ULORIC (febuxostat) tablets, for oral use (February 2019) [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
- Mukoyoshi M, Nishimura S, Hoshide S, Umeda S, Kanou M, Taniguchi K, Muroga H: In vitro drug-drug interaction studies with febuxostat, a novel non-purine selective inhibitor of xanthine oxidase: plasma protein binding, identification of metabolic enzymes and cytochrome P450 inhibition. Xenobiotica. 2008 May;38(5):496-510. doi: 10.1080/00498250801956350. [Article]
- FDA Approved Products: ULORIC (febuxostat) tablets, for oral use (February 2019) [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- 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
- Miyata H, Takada T, Toyoda Y, Matsuo H, Ichida K, Suzuki H: Identification of Febuxostat as a New Strong ABCG2 Inhibitor: Potential Applications and Risks in Clinical Situations. Front Pharmacol. 2016 Dec 27;7:518. doi: 10.3389/fphar.2016.00518. eCollection 2016. [Article]
- Ito F, Miura M, Fujioka Y, Abumiya M, Kobayashi T, Takahashi S, Yoshioka T, Kameoka Y, Takahashi N: The BCRP inhibitor febuxostat enhances the effect of nilotinib by regulation of intracellular concentration. Int J Hematol. 2021 Jan;113(1):100-105. doi: 10.1007/s12185-020-03000-x. Epub 2020 Oct 6. [Article]
- Lehtisalo M, Keskitalo JE, Tornio A, Lapatto-Reiniluoto O, Deng F, Jaatinen T, Viinamaki J, Neuvonen M, Backman JT, Niemi M: Febuxostat, But Not Allopurinol, Markedly Raises the Plasma Concentrations of the Breast Cancer Resistance Protein Substrate Rosuvastatin. Clin Transl Sci. 2020 Nov;13(6):1236-1243. doi: 10.1111/cts.12809. Epub 2020 May 26. [Article]
Drug created at October 18, 2007 23:30 / Updated at April 23, 2024 11:38