Benzbromarone is primarily indicated for the long-term management ofhyperuricemia and chronic gout, especially whenfirst-line treatments like allopurinol fail to reach targetserumuric acid levels or produces intolerableadverse 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]
InEast Asian andSoutheast 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*58:01allele (~10-20% in some populations), which is associated with a 80-100 fold higher risks of serious side effects (DRESS,Stevens-Johnson Syndrome andToxic Epidermal Necrolysis) in allopurinol usage.[15][16][17][18][19][20]
Benzbromarone is a potent uricosuric agent that effectively reduces serum urate levels primarily by inhibiting its renal reabsorption. Its primary target is theSLC22A12 protein on the luminal membrane of theproximal tubule, which is responsible for the majority of urate reabsorption.[2]
It also acts on theSLC2A9 protein, a voltage-driven transporter that moves urate from the tubular cell into the blood, and has mild inhibitory effects onOAT1.[2] Some sources also suggests it may enhance the intestinal elimination of uric acid.[21]
Benzbromarone is partially absorbed followingoral administration, withCmax achieved within 2-3 hours. It is extensively metabolized in the liver, primarily byCYP2C9.[2]
The major metabolite of benzbromarone, 6-hydroxybenzbromarone, retains potent uricosuric activity and has a significantly longerhalf-life (up to 30 hours) comparing to the parent drug (~3 hours), allowing for benzbromarone's once-daily dosing.[2][22] It iseliminated primarily via biliary excretion into thefeces, with urinary excretion accounting for only about 8% of the administered dose.[2][22]
Benzbromarone is a very potentinhibitor of CYP2C9.[4][23] Severalanalogues of the drug have been developed as CYP2C9 andCYP2C19 inhibitors for use in research.[24][25] It has also been reported to targettubulin, blocking its polymerization.[26]
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 asjaundice,choluria, or fatalfulminant hepatitis.[2][5] Therefore, regular monitoring ofliver function is advised, particularly within the first six months of therapy.[27][28]
Like all uricosuric agents, benzbromarone increases the risk ofkidney stones andrenal 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]
Due to its potent CYP2C9 inhibition effects, benzbromarone can significantly increase the serum concentrations of drugs metabolized by this enzyme, notablywarfarin and othercoumarin anticoagulants.[32] This interaction drastically potentiates theanticoagulant effect and substantially increases the risk ofbleeding. Concurrent use is contraindicated or, if unavoidable, requires close monitoring of theinternational 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-doseaspirin or othersalicylates 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.
Benzbromarone was introduced in the 1970s and was viewed as having few associated serious adverse reactions. It was registered in more than 20 countries throughoutEurope,Asia andSouth America, but never approved in theUnited 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 inChina andJapan).[13][15][27][35]
^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.ISBN978-1-4757-1435-7.
^abKumar 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.PMID16815961.
^abcdLee 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.PMID18636784.S2CID1204662.
^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.PMID338280.S2CID8198915.
^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.PMID7033016.S2CID33337546.
^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.PMID18250112.
^abWu, 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.ISSN0770-3198.
^Fujimori, S.; Ooyama, K.; Ooyama, H.; Moromizato, H. (2011). "Efficacy of Benzbromarone in Hyperuricemic Patients Associated with Chronic Kidney Disease".Nucleosides, Nucleotides and Nucleic Acids.30 (12):1035–1038.doi:10.1080/15257770.2011.622732.ISSN1525-7770.
^abLai, 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.ISSN1439-7595.
^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.PMID15615526.
^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.
^Ye, Xiaolan; Wu, Jian; Tang, Kun; Li, Wenge; Xiong, Cunquan; Zhuo, Li (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.ISSN0025-7974.{{cite journal}}: CS1 maint: article number as page number (link)
^Zhu, Wei-Hong; Huang, Ke-Ke; Zhang, Xin-Yi; Deng, Bao-Zhu (2024-11-30). "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.ISSN1750-8460.
^abTakahashi, H; Sato, T; Shimoyama, Y; Shioda, N; Shimizu, T; Kubo, S; Tamura, N; Tainaka, H; Yasumori, T; Echizen, H (1999). "Potentiation of anticoagulant effect of warfarin caused by enantioselective metabolic inhibition by the uricosuric agent benzbromarone".Clinical Pharmacology & Therapeutics.66 (6):569–581.doi:10.1053/cp.1999.v66.103378001.
^Shimodaira, Hideo; Takahashi, Kiyoe; Kano, Kimiko; Matsumoto, Yusuke; Uchida, Yutaka; Kudo, Tatsuhiko (1996). "Enhancement of Anticoagulant Action by Warfarin—Benzbromarone Interaction".The Journal of Clinical Pharmacology.36 (2):168–174.doi:10.1002/j.1552-4604.1996.tb04182.x.ISSN0091-2700.
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