Details
Stereochemistry | ACHIRAL |
Molecular Formula | C17H12Br2O3 |
Molecular Weight | 424.0831 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CCc1c(c2ccccc2o1)C(=O)c3cc(c(c(c3)Br)O)Br
InChI
InChIKey=WHQCHUCQKNIQEC-UHFFFAOYSA-N
InChI=1S/C17H12Br2O3/c1-2-13-15(10-5-3-4-6-14(10)22-13)16(20)9-7-11(18)17(21)12(19)8-9/h3-8,21H,2H2,1H3
DescriptionSources: http://www.ncbi.nlm.nih.gov/pubmed/18636784
Sources: http://www.ncbi.nlm.nih.gov/pubmed/18636784
Benzbromarone (INN) is a uricosuric agent and non-competitive inhibitor of xanthine oxidase used in the treatment of gout, especially when the first line treatment, allopurinol, fails or produces intolerable adverse effects. It is structurally related to the antiarrhythmic amiodarone. Benzbromarone was introduced in the 1970s and was viewed as having few associated serious adverse reactions. It was registered in about 20 countries throughout Asia, South America and Europe. In 2003, the drug was withdrawn by Sanofi-Synthélabo, after reports of serious hepatotoxicity, although it is still marketed in several countries by other drug companies. The withdrawal has greatly limited its availability around the world and increased difficulty in accessing it in other countries where it has never been available. Standard dosages of benzbromarone (100 mg/day) tend to produce greater hypouricaemic effects than standard doses of allopourinol (300 mg/day) or probenecid (1000 mg/day). Adverse effects associated with benzbromarone are relatively infrequent but potentially severe. Four cases of benzbromarone-induced hepatotoxicity were identified from primary literature, and eleven cases have been reported by Sanofi-Synthélabo but details are not available in the public domain. Only one of the four publicly published cases demonstrated a clear relationship between the drug and liver injury as demonstrated by rechallenge. The other three cases lacked incontrovertible evidence to support a diagnosis of benzbromarone-induced hepatotoxicity. If all the reported cases are assumed to be due to benzbromarone, the estimated risk of hepatotoxicity in Europe was approximately 1 in 17 000 patients but may be higher in Japan. Benzbromarone is a very potent inhibitor of CYP2C9. The mechanism of benzbromarone hepatotoxicity is believed to be due to its hepatic metabolism by CYP2C9 and possible effects of the parent compound or its metabolites on mitochondrial function. Benzbromarone is a benzofuran and shares structural similarities with benzarone and amiodarone, all three of which affect mitochondrial function.
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
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Target ID: CHEMBL1929 Sources: https://www.ncbi.nlm.nih.gov/pubmed/1206675 |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Sources: http://www.ncbi.nlm.nih.gov/pubmed/18636784 |
Curative | EXURATE Approved UseFor the chronic management of hyperuricemia in patients with gout. |
PubMed
Title | Date | PubMed |
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Potentiation of anticoagulant effect of warfarin caused by enantioselective metabolic inhibition by the uricosuric agent benzbromarone. | 1999 Dec |
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[Vesical uric acid lithiasis in a child with renal hypouricemia]. | 2001 Sep |
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Fulminant hepatic failure associated with benzbromarone treatment: a case report. | 2002 May |
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Flavonoids as inhibitors of MRP1-like efflux activity in human erythrocytes. A structure-activity relationship study. | 2003 |
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[Drug therapy for idiopathic hyperuricemia--introduction, dose, and side effects]. | 2003 Jan |
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A new class of CYP2C9 inhibitors: probing 2C9 specificity with high-affinity benzbromarone derivatives. | 2003 Jul |
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Effects of aspirin and/or salicylate on hydrolysis and glucuronidation of indomethacin in rat erythrocytes and hepatocytes. | 2003 May |
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[Chronic gout. Case report of a severe course of disease]. | 2003 Nov 15 |
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Management of acute and chronic gouty arthritis: present state-of-the-art. | 2004 |
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Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion. | 2004 Jan |
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Spinal tophaceous gout mimicking a spinal tumor. | 2004 Jul |
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Differential multidrug resistance-associated protein 1 through 6 isoform expression and function in human intestinal epithelial Caco-2 cells. | 2004 Nov |
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Gout in solid organ transplantation: a challenging clinical problem. | 2005 |
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Mechanisms of benzarone and benzbromarone-induced hepatic toxicity. | 2005 Apr |
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Sulfasalazine transport in in-vitro, ex-vivo and in-vivo absorption models: contribution of efflux carriers and their modulation by co-administration of synthetic nature-identical fruit extracts. | 2005 Dec |
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Involvement of uric acid transporter in increased renal clearance of the xanthine oxidase inhibitor oxypurinol induced by a uricosuric agent, benzbromarone. | 2005 Dec |
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Phenothiazine maleates stimulate MRP1 transport activity in human erythrocytes. | 2005 Dec 30 |
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Inhibition of MRP1-mediated efflux in human erythrocytes by mono-anionic bile salts. | 2005 Sep-Oct |
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Utilization of a one-dimensional score for surveying chemical-induced changes in expression levels of multiple biomarker gene sets using a large-scale toxicogenomics database. | 2006 Dec |
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[Molecular mechanism in biological transport in the kidney: Urate transporter URAT1]. | 2006 Feb |
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Effect of fenofibrate in combination with urate lowering agents in patients with gout. | 2006 Jun |
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A convergent synthetic study of biologically active benzofuran derivatives. | 2006 Jun |
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Micellar electrokinetic capillary chromatographic method for the quantitative analysis of uricosuric and antigout drugs in pharmaceutical preparations. | 2006 Jun |
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A causal role for uric acid in fructose-induced metabolic syndrome. | 2006 Mar |
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Antihyperuricemic lignans from the leaves of Phyllanthus niruri. | 2006 Nov |
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[The inhibition of CYP2C9 isoenzyme in Cunninghamella blakesleeana AS 3. 910]. | 2006 Oct |
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Activating effect of benzbromarone, a uricosuric drug, on peroxisome proliferator-activated receptors. | 2007 |
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Emerging therapies in the long-term management of hyperuricaemia and gout. | 2007 Apr |
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Pseudotumor of gout in the patella of a kidney transplant recipient. | 2007 Jun |
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Correctors promote maturation of cystic fibrosis transmembrane conductance regulator (CFTR)-processing mutants by binding to the protein. | 2007 Nov 16 |
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Flow cytometric monitoring of multidrug drug resistance protein 1 (MRP1/ABCC1) -mediated transport of 2',7'-bis-(3-carboxypropyl)-5-(and-6)- carboxyfluorescein (BCPCF) into human erythrocyte membrane inside-out vesicles. | 2007 Sep-Dec |
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Modeling and synthesis of novel tight-binding inhibitors of cytochrome P450 2C9. | 2008 Apr 1 |
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Effect of hypouricaemic and hyperuricaemic drugs on the renal urate efflux transporter, multidrug resistance protein 4. | 2008 Dec |
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Modulation of sinusoidal and canalicular elimination of bilirubin-glucuronides by rifampicin and other cholestatic drugs in a sandwich culture of rat hepatocytes. | 2008 Mar |
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Efficacy and tolerability of urate-lowering drugs in gout: a randomised controlled trial of benzbromarone versus probenecid after failure of allopurinol. | 2009 Jan |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: http://www.ncbi.nlm.nih.gov/pubmed/18636784
The usual dose: 100mg per day
50 – 200 mg per day may be used
Route of Administration:
Oral
In Vitro Use Guide
Sources: http://www.ncbi.nlm.nih.gov/pubmed/26693855
Microsomes from human livers were preincubated with benzbromarone and NADPH, followed by evaluation of CYP2C9 and CYP3A4 activities.
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Classification Tree | Code System | Code | ||
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WHO-ATC |
M04AB03
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WHO-VATC |
QM04AB03
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LIVERTOX |
96
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NCI_THESAURUS |
C921
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Code System | Code | Type | Description | ||
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BENZBROMARONE
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DB12319
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318
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3562-84-3
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CHEMBL388590
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222-630-7
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3562-84-3
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M2337
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4POG0RL69O
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2333
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SUB05743MIG
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1385
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C74412
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1427
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D001553
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ACTIVE MOIETY
METABOLITE (PARENT)