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Published in Caroline Ashley, Aileen Dunleavy, John Cunningham, The Renal Drug Handbook, 2018
Caroline Ashley, Aileen Dunleavy, John Cunningham
Biological effect of 100 mg benzbromarone is equivalent to 1.5 g probenecid or greater than 300 mg of allopurinol. (Masbernard A. Ten years’ experience with benzbromarone in the management of gout and hyperuricaemia. SAMJ. 1981; 59(20): 701–6.)
Crystal deposition disorders
Published in Ashley W. Blom, David Warwick, Michael R. Whitehouse, Apley and Solomon’s System of Orthopaedics and Trauma, 2017
Paul Creamer, Dimitris Kassimos
Other ULT agents are ‘uricosuric’, increasing excretion of urate at the kidney. In general they are less effective than allopurinol and are contraindicated in urolithiasis. Examples include probenecid and sulphinpyrazone, which act by inhibiting URAT1. Benzbromarone is an effective uricosuric but is not widely available.
Advances in pharmacotherapies for hyperuricemia
Published in Expert Opinion on Pharmacotherapy, 2023
Federica Piani, Davide Agnoletti, Claudio Borghi
Benzbromarone has been the most widely used uricosuric drug for the treatment of gout. Currently, it is available only in Germany, The Netherlands, and Spain due to concerns around its hepatotoxicity [60]. Benzbromarone acts inhibiting URAT1 and GLUT9, the latter possibly being involved in both the reabsorption and the secretion of uric acid in the proximal tubule [59]. Its use is only approved in monotherapy, except for Germany that allows the combination with XO inhibitors. The usual dosage goes from 50 to 100 mg once/daily, the peak concentration is reached within 2 h and the half-life goes from 4 to 17 h [32]. Due to its potential hepatotoxicity, it is recommended to check serum transaminases every 3 months [60]. A common side effect is diarrhea and caution is needed for concomitant treatments with CYP2C9-metabolized drugs such as warfarin. Finally, although mainly metabolized by the liver, benzbromarone should not be administered in severe kidney failure (eGFR<20 ml/min).
What’s new on the front-line of gout pharmacotherapy?
Published in Expert Opinion on Pharmacotherapy, 2022
Kurt E. G. Blake, Jordan L. Saag, Kenneth G Saag
Benzbromarone potently inhibits URAT1 channels in the nephron. In 2003, it was originally withdrawn from the European market as a result of growing concerns about fatal hepatoxicity. The mechanism of this is not clear but is thought to be related to induced respiratory chain and beta-oxidation defects leading mitochondrial toxicity [72]. Clinicians have opined that the withdrawal may have been influenced more by medicolegal and commercial concerns, rather than from pharmacovigilance [73]. A review of the National Institutes of Health (NIH) LiverTox database revealed 13 case reports documenting severe hepatic toxicity from benzbromarone between the years 1987 and 2016. During this period 4 patients died [74]. Additionally, the safety and efficacy of benzbromarone was compared to allopurinol and probenecid in a systematic review and network metanalysis. Fifteen RCTs with a total of 7246 patients were reviewed. Pairwise metanalysis showed no statistically significant difference between benzbromarone vs allopurinol or benzbromarone vs probenecid regarding safety. Network metanalysis also showed no statistically significant difference in efficacy between benzbromarone vs. febuxostat doses up to 80 mg/day or benzbromarone vs allopurinol [75]. Today, benzbromarone is available for limited distribution in Asian and South American Markets. It is also available in Spain, the Netherlands, and New Zealand and is among the uricosuric options endorsed by EULAR [37]. Benzbromarone has never been approved by the FDA.
Recent approaches to gout drug discovery: an update
Published in Expert Opinion on Drug Discovery, 2020
Naoyuki Otani, Motoshi Ouchi, Hideo Kudo, Shuichi Tsuruoka, Ichiro Hisatome, Naohiko Anzai
Benzbromarone was the first compound developed as a uricosuric agent in the 1970 s. Although its molecular mechanism was not elucidated at the time of development, it has since been clarified that it acts in the luminal membrane of renal proximal tubules by inhibiting URAT1, which reabsorbs urate excreted into the urine. Thus, benzbromarone promotes the excretion of urate [24]. This drug inhibits URAT1 in a concentration-dependent manner with an IC50 of 22 nM, indicating a potent inhibitor [50]. Because of its adverse reactions, including liver dysfunction and fulminant hepatitis, benzbromarone was not approved in the United States and withdrawn from the market in Europe in 2003 [51]. Reinders et al. [52] in the Netherlands conducted a prospective study on 32 cases and reported that switching from 100–200 mg of benzbromarone to 200–300 mg of allopurinol significantly increased serum urate levels, and the percentage of subjects reaching the target urate level of 5 mg/dl fell from 92% to 25%. The authors concluded that benzbromarone had a more potent urate-lowering effect than allopurinol and criticized the withdrawal of benzbromarone from the European market. Benzbromarone is considered an excellent drug for reducing urate, and drug discovery based on benzbromarone is progressing. URC-102 [53] and dotinurad (FYU-981) [54], which are described below, are structural derivatives of benzbromarone.