Benzbromarone

Benzbromarone
Clinical data
Trade namesUrinorm, Desuric, Normurat, Narcaricin, others
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
ATC code
Pharmacokinetic data
Bioavailability~50%
Protein binding>99%
MetabolismLiver (CYP2C9)
Elimination half-life3 hours (30 hours for main active metabolite 6-hydroxybenzbromarone)
ExcretionMainly feces
Urine (8%)
Identifiers
  • (3,5-dibromo-4-hydroxyphenyl)-(2-ethyl-1-benzofuran-3-yl)methanone
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.020.573
Chemical and physical data
FormulaC17H12Br2O3
Molar mass424.088 g·mol−1
3D model (JSmol)
Melting point161 to 163 °C (322 to 325 °F)
  • Brc1cc(cc(Br)c1O)C(=O)c2c3ccccc3oc2CC
  • 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 Y
  • Key:WHQCHUCQKNIQEC-UHFFFAOYSA-N Y
 NY (what is this?)  (verify)

Benzbromarone is a uricosuric agent and weak non-competitive inhibitor of xanthine oxidase used in the treatment of gout.[1][2] It is a brominated analogue of withdrawn uricosuric benziodarone and benzarone, and is structurally related to the antiarrhythmic amiodarone.[3][4]

Benzbromarone was withdrawn from most European countries in 2003 due to the risk of idiosyncratic hepatotoxicity, but remains heavily used in Asia and South America.[5] Despite this risk, it is generally considered highly effective and well tolerated in most patients.[6][7][8][9] Clinical trials dating back to 1981 and as recent as 2022, as well as meta-analyses, have reported its superior efficacy compared to both non-uricosuric xanthine oxidase inhibitors (allopurinol and febuxostat) and another uricosuric drug, probenecid.[2][10][11][12][13]

Medical uses

Benzbromarone is primarily indicated for the long-term management of hyperuricemia and chronic gout, especially when first-line treatments like allopurinol fail to reach target serum uric acid levels or produces intolerable adverse effects.[2][8] It is particularly effective in "underexcretors" (patients with fractional excretion of urate <5.5% and uric acid excretion ≤600 mg/day/1.73 m2), and unlike other uricosurics, is still effective in patients with mild to moderate renal insufficiency (eGFR as low as 20-30 mL/min/1.73 m2).[12][14]

In East Asian and Southeast Asian countries, benzbromarone is widely considered a first-line treatment, and along with febuxostat, are usually prescribed over allopurinol in gout, particularly due to a significantly more common prevalence of HLA-B*58:01 allele (~10-20% in some populations), which is associated with a 80-100 fold higher risks of serious side effects (DRESS, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis) in allopurinol usage.[15][16][17][18][19][20]

Pharmacology

Mechanism of action

Benzbromarone is a potent uricosuric agent that effectively reduces serum urate levels primarily by inhibiting its renal reabsorption. Its primary target is the SLC22A12 protein on the luminal membrane of the proximal tubule, which is responsible for the majority of urate reabsorption.[2]

It also acts on the SLC2A9 protein, a voltage-driven transporter that moves urate from the tubular cell into the blood, and has mild inhibitory effects on OAT1.[2] Some sources also suggests it may enhance the intestinal elimination of uric acid.[21]

Pharmacokinetics

Benzbromarone is partially absorbed following oral administration, with Cmax achieved within 2-3 hours. It is extensively metabolized in the liver, primarily by CYP2C9.[2]

The major metabolite of benzbromarone, 6-hydroxybenzbromarone, retains potent uricosuric activity and has a significantly longer half-life (up to 30 hours) comparing to the parent drug (~3 hours), allowing for benzbromarone's once-daily dosing.[2][22] It is eliminated primarily via biliary excretion into the feces, with urinary excretion accounting for only about 8% of the administered dose.[2][22]

Benzbromarone is a very potent inhibitor of CYP2C9.[4][23] Several analogues of the drug have been developed as CYP2C9 and CYP2C19 inhibitors for use in research.[24][25] It has also been reported to target tubulin, blocking its polymerization.[26]

Side effects

The most serious side effect of benzbromarone is idiosyncratic liver injury (with a risk of 1/17000 in Europe and possibly higher in Japan), which can manifest as jaundice, choluria, or fatal fulminant hepatitis.[2][5] Therefore, regular monitoring of liver function is advised, particularly within the first six months of therapy.[27][28]

Common side effects include diarrhea (3-4%), nausea, vomiting, and abdominal discomfort.[29] Rarely, patients may experience skin rashes, fever, headache, dizziness, or alopecia.

Like all uricosuric agents, benzbromarone increases the risk of kidney stones and renal colic by promoting uric acid excretion.[28][30] To mitigate this risk, maintaining high fluid intake combined with urinary alkalinization (e.g. sodium bicarbonate) is essential to minimizing crystal formation.[31]

Drug interactions

Due to its potent CYP2C9 inhibition effects, benzbromarone can significantly increase the serum concentrations of drugs metabolized by this enzyme, notably warfarin and other coumarin anticoagulants.[32] This interaction drastically potentiates the anticoagulant effect and substantially increases the risk of bleeding. Concurrent use is contraindicated or, if unavoidable, requires close monitoring of the international normalized ratio and a substantial reduction in the anticoagulant dose (one study shows a 36% reduction in daily warfarin dosage might be required).[32][33]

High-dose aspirin or other salicylates can antagonize the uricosuric effect of benzbromarone.[34]

Benzbromarone should not be used with other uricosuric agents as it may lead to excessive uric acid excretion and increase the risk of kidney stones.

History

Benzbromarone was introduced in the 1970s and was viewed as having few associated serious adverse reactions. It was registered in more than 20 countries throughout Europe, Asia and South America, but never approved in the United States.[5]

In 2003, benzbromarone was withdrawn by Sanofi-Synthélabo in most of Europe, after reports of serious idiosyncratic hepatotoxicity,[5] although it is still marketed in several countries by other drug companies, and remains a popular first-line drug in Asia (especially in China and Japan).[13][15][27][35]

References

  1. ^ Sinclair DS, Fox IH (December 1975). "The pharmacology of hypouricemic effect of benzbromarone". The Journal of Rheumatology. 2 (4): 437–445. PMID 1206675.
  2. ^ a b c d e f g h i Azevedo VF, Kos IA, Vargas-Santos AB, da Rocha Castelar Pinheiro G, Dos Santos Paiva E (August 2019). "Benzbromarone in the treatment of gout". Advances in Rheumatology. 59 (1) 37. doi:10.1186/s42358-019-0080-x. PMID 31391099.
  3. ^ de Gery A, Auscher C, Saporta L, Delbarre F (1974). "Treatment of Gout and Hyperuricaemia by Benzbromarone Ethyl 2 (Dibromo -3,5 Hydroxy - 4 Benzoyl) - 3 Benzofuran". Purine Metabolism in Man. Advances in Experimental Medicine and Biology. Vol. 41. New York, NY: Springer US. pp. 683–689. doi:10.1007/978-1-4757-1433-3_40. ISBN 978-1-4757-1435-7. PMID 4598966.
  4. ^ a b Kumar V, Locuson CW, Sham YY, Tracy TS (October 2006). "Amiodarone analog-dependent effects on CYP2C9-mediated metabolism and kinetic profiles". Drug Metabolism and Disposition. 34 (10): 1688–1696. doi:10.1124/dmd.106.010678. PMID 16815961.
  5. ^ a b c d Lee MH, Graham GG, Williams KM, Day RO (2008). "A benefit-risk assessment of benzbromarone in the treatment of gout. Was its withdrawal from the market in the best interest of patients?". Drug Safety. 31 (8): 643–665. doi:10.2165/00002018-200831080-00002. PMID 18636784. S2CID 1204662.
  6. ^ Heel RC, Brogden RN, Speight TM, Avery GS (November 1977). "Benzbromarone: a review of its pharmacological properties and therapeutic use in gout and hyperuricaemia". Drugs. 14 (5): 349–366. doi:10.2165/00003495-197714050-00002. PMID 338280. S2CID 8198915.
  7. ^ Masbernard A, Giudicelli CP (May 1981). "Ten years' experience with benzbromarone in the management of gout and hyperuricaemia" (PDF). South African Medical Journal = Suid-Afrikaanse Tydskrif vir Geneeskunde. 59 (20): 701–706. PMID 7221794. Archived from the original (PDF) on 2021-11-04. Retrieved 2013-04-16.
  8. ^ a b Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, Herrero-Beites A, García-Erauskin G, Ruiz-Lucea E (September 1998). "Efficacy of allopurinol and benzbromarone for the control of hyperuricaemia. A pathogenic approach to the treatment of primary chronic gout". Annals of the Rheumatic Diseases. 57 (9): 545–549. doi:10.1136/ard.57.9.545. PMC 1752740. PMID 9849314.
  9. ^ Reinders MK, van Roon EN, Houtman PM, Brouwers JR, Jansen TL (September 2007). "Biochemical effectiveness of allopurinol and allopurinol-probenecid in previously benzbromarone-treated gout patients". Clinical Rheumatology. 26 (9): 1459–1465. doi:10.1007/s10067-006-0528-3. PMID 17308859.
  10. ^ Schepers GW (1981). "Benzbromarone therapy in hyperuricaemia; comparison with allopurinol and probenecid". The Journal of International Medical Research. 9 (6): 511–515. doi:10.1177/030006058100900615. PMID 7033016. S2CID 33337546.
  11. ^ Reinders MK, van Roon EN, Jansen TL, Delsing J, Griep EN, Hoekstra M, et al. (January 2009). "Efficacy and tolerability of urate-lowering drugs in gout: a randomised controlled trial of benzbromarone versus probenecid after failure of allopurinol". Annals of the Rheumatic Diseases. 68 (1): 51–56. doi:10.1136/ard.2007.083071. PMID 18250112.
  12. ^ a b Yan F, Xue X, Lu J, Dalbeth N, Qi H, Yu Q, et al. (December 2022). "Superiority of Low-Dose Benzbromarone to Low-Dose Febuxostat in a Prospective, Randomized Comparative Effectiveness Trial in Gout Patients With Renal Uric Acid Underexcretion". Arthritis & Rheumatology. 74 (12): 2015–2023. doi:10.1002/art.42266. PMC 9771863. PMID 35795968.
  13. ^ a b Wu F, Chen L, Du Y (May 2024). "Comparison of the efficacy and safety of benzbromarone and febuxostat in gout and hyperuricemia: a systematic review and meta-analysis". Clinical Rheumatology. 43 (5): 1745–1754. doi:10.1007/s10067-024-06933-4. PMID 38492092.
  14. ^ Fujimori S, Ooyama K, Ooyama H, Moromizato H (December 2011). "Efficacy of benzbromarone in hyperuricemic patients associated with chronic kidney disease". Nucleosides, Nucleotides & Nucleic Acids. 30 (12): 1035–1038. doi:10.1080/15257770.2011.622732. PMID 22132953.
  15. ^ a b Lai SW, Liao KF, Hwang BF, Liu CS (December 2023). "Real-world treatment of gout and asymptomatic hyperuricaemia in Japan". Modern Rheumatology. 34 (1): 245–246. doi:10.1093/mr/road006. PMID 36658713.
  16. ^ Pham HT, Tran MH, Mai Hoang TV, Nguyen AH, Tran MH (August 2025). "HLA-B*58:01 genotyping prevalence and the association with allopurinol-induced severe cutaneous adverse reactions: a living systematic review and meta-analysis". Scientific Reports. 15 (1) 30742. doi:10.1038/s41598-025-16062-w. PMC 12371011. PMID 40841814.
  17. ^ Hung SI, Chung WH, Liou LB, Chu CC, Lin M, Huang HP, et al. (March 2005). "HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol". Proceedings of the National Academy of Sciences of the United States of America. 102 (11): 4134–4139. doi:10.1073/pnas.0409500102. PMC 554812. PMID 15743917.
  18. ^ Somkrua R, Eickman EE, Saokaew S, Lohitnavy M, Chaiyakunapruk N (September 2011). "Association of HLA-B*5801 allele and allopurinol-induced Stevens Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis". BMC Medical Genetics. 12 (1) 118. doi:10.1186/1471-2350-12-118. PMC 3189112. PMID 21906289.
  19. ^ Dean L (March 2016). "Allopurinol Therapy and HLA-B*58:01 Genotype". In Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520356.
  20. ^ Ng CY, Yeh YT, Wang CW, Hung SI, Yang CH, Chang YC, et al. (July 2016). "Impact of the HLA-B(*)58:01 Allele and Renal Impairment on Allopurinol-Induced Cutaneous Adverse Reactions". The Journal of Investigative Dermatology. 136 (7): 1373–1381. doi:10.1016/j.jid.2016.02.808. PMID 26996548.
  21. ^ Hosomi A, Nakanishi T, Fujita T, Tamai I (2012-02-10). "Extra-renal elimination of uric acid via intestinal efflux transporter BCRP/ABCG2". PLOS ONE. 7 (2) e30456. doi:10.1371/journal.pone.0030456. PMC 3277506. PMID 22348008.
  22. ^ a b Keith MP, Gilliland WR, Uhl K (2009). "GOUT". Pharmacology and Therapeutics. Elsevier. pp. 1039–1046. doi:10.1016/b978-1-4160-3291-5.50079-2. ISBN 978-1-4160-3291-5.
  23. ^ Hummel MA, Locuson CW, Gannett PM, Rock DA, Mosher CM, Rettie AE, et al. (September 2005). "CYP2C9 genotype-dependent effects on in vitro drug-drug interactions: switching of benzbromarone effect from inhibition to activation in the CYP2C9.3 variant". Molecular Pharmacology. 68 (3): 644–651. doi:10.1124/mol.105.013763. PMC 1552103. PMID 15955872.
  24. ^ Locuson CW, Rock DA, Jones JP (June 2004). "Quantitative binding models for CYP2C9 based on benzbromarone analogues". Biochemistry. 43 (22): 6948–6958. CiteSeerX 10.1.1.127.2015. doi:10.1021/bi049651o. PMID 15170332.
  25. ^ Locuson CW, Suzuki H, Rettie AE, Jones JP (December 2004). "Charge and substituent effects on affinity and metabolism of benzbromarone-based CYP2C19 inhibitors". Journal of Medicinal Chemistry. 47 (27): 6768–6776. doi:10.1021/jm049605m. PMID 15615526.
  26. ^ Baksheeva V, La Rocca R, Allegro D, Derviaux C, Pasquier E, Roche P, et al. (August 2025). "NanoDSF Screening for Anti-tubulin Agents Uncovers New Structure-Activity Insights". Journal of Medicinal Chemistry. 68 (16): 17485–17498. doi:10.1021/acs.jmedchem.5c01008. PMC 12406199. PMID 40815226.
  27. ^ a b Ishii T, Hoshino K, Honda M, Yamana Y, Sasaki-Tanaka R, Kumagawa M, et al. (2022-03-08). "A Case of Recent Liver Injury Induced by Benzbromarone". Reports. 5 (1): 8. doi:10.3390/reports5010008. ISSN 2571-841X.
  28. ^ a b Azevedo VF, Buiar PG, Giovanella LH, Severo CR, Carvalho M (2014). "Allopurinol, benzbromarone, or a combination in treating patients with gout: analysis of a series of outpatients". International Journal of Rheumatology. 2014 263720. doi:10.1155/2014/263720. PMC 3955622. PMID 24719620.
  29. ^ Straube S (2010). "Anti-inflammatory and antipyretic analgesics and drugs used in gout". Side Effects of Drugs Annual. Vol. 32. Elsevier. pp. 225–241. doi:10.1016/s0378-6080(10)32009-5. ISBN 978-0-444-53550-4.
  30. ^ Ye X, Wu J, Tang K, Li W, Xiong C, Zhuo L (April 2019). "Benzbromarone as a possible cause of acute kidney injury in patients with urolithiasis: Two case reports". Medicine. 98 (15) e15214. doi:10.1097/MD.0000000000015214. PMC 6485891. PMID 30985721.
  31. ^ Zhu WH, Huang KK, Zhang XY, Deng BZ (November 2024). "Analysis of the Efficacy and Safety of Benzbromarone Combined with Sodium Bicarbonate Tablets in the Treatment of Hyperuricemia". British Journal of Hospital Medicine. 85 (11): 1–12. doi:10.12968/hmed.2024.0453. PMID 39618203.
  32. ^ a b Takahashi H, Sato T, Shimoyama Y, Shioda N, Shimizu T, Kubo S, et al. (December 1999). "Potentiation of anticoagulant effect of warfarin caused by enantioselective metabolic inhibition by the uricosuric agent benzbromarone". Clinical Pharmacology and Therapeutics. 66 (6): 569–581. doi:10.1053/cp.1999.v66.103378001. PMID 10613612.
  33. ^ Shimodaira H, Takahashi K, Kano K, Matsumoto Y, Uchida Y, Kudo T (February 1996). "Enhancement of anticoagulant action by warfarin-benzbromarone interaction". Journal of Clinical Pharmacology. 36 (2): 168–174. doi:10.1002/j.1552-4604.1996.tb04182.x. PMID 8852393.
  34. ^ Sriranganathan MK (2018). "Benzbromarone: A Review ☆". Reference Module in Biomedical Sciences. Elsevier. doi:10.1016/b978-0-12-801238-3.97769-9. ISBN 978-0-12-801238-3.
  35. ^ Xue X, Yuan X, Han L, Li X, Merriman TR, Cui L, et al. (2022-01-17). "Effect of Clinical Typing on Serum Urate Targets of Benzbromarone in Chinese Gout Patients: A Prospective Cohort Study". Frontiers in Medicine. 8 806710. doi:10.3389/fmed.2021.806710. PMC 8801777. PMID 35111784.
This article is issued from Wikipedia. The text is available under Creative Commons Attribution-Share Alike 4.0 unless otherwise noted. Additional terms may apply for the media files.