Benzbromarone

Last updated
Benzbromarone
Benzbromarone.svg
Clinical data
AHFS/Drugs.com International Drug Names
ATC code
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 InfoCard 100.020.573 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H12Br2O3
Molar mass 424.088 g·mol−1
3D model (JSmol)
Melting point 161 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 Yes check.svgY
  • Key:WHQCHUCQKNIQEC-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Benzbromarone is a uricosuric agent and weak non-competitive inhibitor of xanthine oxidase [1] used in the treatment of gout, especially when allopurinol, a first-line treatment, fails or produces intolerable adverse effects. It is a brominated analogue of withdrawn uricosuric benziodarone and benzarone, and it is structurally related to the antiarrhythmic amiodarone. [2] [3]

Contents

Despite the risk of idiosyncratic hepatotoxicity, benzbromarone is generally considered highly effective and well tolerated in most patients. [4] [5] [6] [7] Clinical trials dating back to 1981 and as recent as 2008, along with subsequent meta-analyses, have reported its superior efficacy compared to both non-uricosuric xanthine oxidase inhibitors (allopurinol and febuxostat) and another uricosuric drug, probenecid. [8] [9] [10]

Mechanism of action

Benzbromarone is a very potent inhibitor of CYP2C9. [3] [11] Several analogues of the drug have been developed as CYP2C9 and CYP2C19 inhibitors for use in research. [12] [13] It has also been reported to target tubulin, blocking its polymerization. [14]

History

Benzbromarone was introduced in the 1970s and was viewed as having few associated serious adverse reactions. It was registered in about 20 countries throughout Europe, Asia and South America, but never approved in the United States. [15]

In 2003, the drug was withdrawn by Sanofi-Synthélabo in Europe, after reports of serious hepatotoxicity, [15] although it is still marketed in several countries by other drug companies, and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). [10] [16] [17] [18] In these East Asian countries, benzbromarone and 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. [18] [19] [20] [21] [22] [23]

References

  1. ↑ Sinclair DS, Fox IH (December 1975). "The pharmacology of hypouricemic effect of benzbromarone". The Journal of Rheumatology. 2 (4): 437–45. PMID   1206675.
  2. ↑ 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. Vol. 41. New York, NY: Springer US. p. 683–689. doi:10.1007/978-1-4757-1433-3_40. ISBN   978-1-4757-1435-7 . Retrieved 2026-02-06.
  3. 1 2 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): 1688–96. doi:10.1124/dmd.106.010678. PMID   16815961.
  4. ↑ 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): 349–66. doi:10.2165/00003495-197714050-00002. PMID   338280. S2CID   8198915.
  5. ↑ 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): 701–6. PMID   7221794. Archived from the original (PDF) on 2021-11-04. Retrieved 2013-04-16.
  6. ↑ 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): 545–9. doi:10.1136/ard.57.9.545. PMC   1752740 . PMID   9849314.
  7. ↑ 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): 1459–65. doi: 10.1007/s10067-006-0528-3 . PMID   17308859.
  8. ↑ Schepers GW (1981). "Benzbromarone therapy in hyperuricaemia; comparison with allopurinol and probenecid". The Journal of International Medical Research. 9 (6): 511–5. doi:10.1177/030006058100900615. PMID   7033016. S2CID   33337546.
  9. ↑ 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): 51–6. doi:10.1136/ard.2007.083071. PMID   18250112.
  10. 1 2 Wu, Fan; Chen, Lvyi; Du, Yimei (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. ISSN   0770-3198 . Retrieved 2026-02-06.
  11. ↑ Hummel MA, Locuson CW, Gannett PM, Rock DA, Mosher CM, Rettie AE, Tracy TS (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): 644–51. doi:10.1124/mol.105.013763. PMC   1552103 . PMID   15955872.
  12. ↑ Locuson CW, Rock DA, Jones JP (June 2004). "Quantitative binding models for CYP2C9 based on benzbromarone analogues". Biochemistry. 43 (22): 6948–58. CiteSeerX   10.1.1.127.2015 . doi:10.1021/bi049651o. PMID   15170332.
  13. ↑ 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): 6768–76. doi:10.1021/jm049605m. PMID   15615526.
  14. ↑ Baksheeva VE, La Rocca R, Allegro D, Derviaux C, Pasquier E, Roche P, Morelli X, Devred F, Golovin AV, Tsvetkov PO (2025). "NanoDSF Screening for Anti-tubulin Agents Uncovers New Structure–Activity Insights". Journal of Medicinal Chemistry. doi:10.1021/acs.jmedchem.5c01008.
  15. 1 2 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): 643–65. doi:10.2165/00002018-200831080-00002. PMID   18636784. S2CID   1204662.
  16. ↑ Xue, Xiaomei; Yuan, Xuan; Han, Lin; Li, Xinde; Merriman, Tony R.; Cui, Lingling; Liu, Zhen; Sun, Wenyan; Wang, Can; Yan, Fei; He, Yuwei; Ji, Aichang; Lu, Jie; Li, Changgui (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. doi: 10.3389/fmed.2021.806710 . ISSN   2296-858X. PMC   8801777 . PMID   35111784.
  17. ↑ Ishii, Tomotaka; Hoshino, Keijiro; Honda, Masayuki; Yamana, Yoichiro; Sasaki-Tanaka, Reina; Kumagawa, Mariko; Kanezawa, Shini; Mizutani, Taku; Matsumoto, Naoki; Masuzaki, Ryota; Nirei, Kazushige; Yamagami, Hiroaki; Moriyama, Mitsuhiko; Kanda, Tatsuo (2022-03-08). "A Case of Recent Liver Injury Induced by Benzbromarone". Reports. 5 (1): 8. doi: 10.3390/reports5010008 . ISSN   2571-841X.
  18. 1 2 Lai, Shih-Wei; Liao, Kuan-Fu; Hwang, Bing-Fang; Liu, Chiu-Shong (2023-12-22). "Real-world treatment of gout and asymptomatic hyperuricaemia in Japan". Modern Rheumatology. 34 (1): 245–246. doi:10.1093/mr/road006. ISSN   1439-7595 . Retrieved 2026-02-06.
  19. ↑ Pham, Hong Tham; Tran, Manh Hung; Mai Hoang, Thuy-Van; Nguyen, Ai-Hoc; Tran, Minh-Hoang (2025-08-21). "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). doi:10.1038/s41598-025-16062-w. ISSN   2045-2322. PMC   12371011 . PMID   40841814 . Retrieved 2026-02-06.
  20. ↑ Hung, Shuen-Iu; Chung, Wen-Hung; Liou, Lieh-Bang; Chu, Chen-Chung; Lin, Marie; Huang, Hsien-Ping; Lin, Yen-Ling; Lan, Joung-Liang; Yang, Li-Cheng; Hong, Hong-Shang; Chen, Ming-Jing; Lai, Ping-Chin; Wu, Mai-Szu; Chu, Chia-Yu; Wang, Kuo-Hsien; Chen, Chien-Hsiun; Fann, Cathy S. J.; Wu, Jer-Yuarn; Chen, Yuan-Tsong (2005-03-15). "HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol". Proceedings of the National Academy of Sciences. 102 (11): 4134–4139. doi:10.1073/pnas.0409500102. ISSN   0027-8424. PMC   554812 . PMID   15743917.
  21. ↑ Somkrua, Ratchadaporn; Eickman, Elizabeth E; Saokaew, Surasak; Lohitnavy, Manupat; Chaiyakunapruk, Nathorn (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). doi: 10.1186/1471-2350-12-118 . ISSN   1471-2350. PMC   3189112 . PMID   21906289.
  22. ↑ 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.
  23. ↑ Ng, Chau Yee; Yeh, Yu-Ting; Wang, Chuang-Wei; Hung, Shuen-Iu; Yang, Chih-Hsun; Chang, Ya-Ching; Chang, Wan-Chun; Lin, Yu-Jr; Chang, Chee-Jen; Su, Shih-Chi; Fan, Wen-Lang; Chen, Der-Yuan; Wu, Yeong-Jian Jan; Tian, Ya-Chung; Hui, Rosaline Chung-Yee; Chung, Wen-Hung (2016). "Impact of the HLA-B58:01 Allele and Renal Impairment on Allopurinol-Induced Cutaneous Adverse Reactions". Journal of Investigative Dermatology. 136 (7): 1373–1381. doi:10.1016/j.jid.2016.02.808 . Retrieved 2026-02-06.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.