Benzbromarone

Benzbromarone is a uricosuric agent and 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 structurally related to the antiarrhythmic amiodarone.[2]

Benzbromarone
Clinical data
AHFS/Drugs.comInternational Drug Names
ATC code
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.020.573
Chemical and physical data
FormulaC17H12Br2O3
Molar mass424.083 g/mol g·mol−1
3D model (JSmol)
Melting point161 to 163 °C (322 to 325 °F)
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Benzbromarone is highly effective and well tolerated,[3][4][5][6] and clinical trials as early as 1981 and as recently as April 2008 have suggested it is superior to both allopurinol, a non-uricosuric xanthine oxidase inhibitor, and probenecid, another uricosuric drug.[7][8]

Mechanism of action

Benzbromarone is a very potent inhibitor of CYP2C9.[2][9] Several analogues of the drug have been developed as CYP2C9 and CYP2C19 inhibitors for use in research.[10][11]

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.

In 2003, the drug was withdrawn by Sanofi-Synthélabo, after reports of serious hepatotoxicity, although it is still marketed in several countries by other drug companies.[12]

References
  1. Sinclair, DS; Fox, IH (1975). "The pharmacology of hypouricemic effect of benzbromarone". The Journal of Rheumatology. 2 (4): 437–45. PMID 1206675.
  2. Kumar, V.; Locuson, CW; Sham, YY; Tracy, TS (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.
  3. Heel, R.C.; Brogden, R.N.; Speight, T.M.; Avery, G.S. (1977). "Benzbromarone". Drugs. 14 (5): 349–66. doi:10.2165/00003495-197714050-00002. PMID 338280.
  4. Masbernard, A; Giudicelli, CP (1981). "Ten years' experience with benzbromarone in the management of gout and hyperuricaemia" (PDF). South African Medical Journal. 59 (20): 701–6. PMID 7221794.
  5. Perez-Ruiz, F; Alonso-Ruiz, A; Calabozo, M; Herrero-Beites, A; Garcia-Erauskin, G; Ruiz-Lucea, E (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.
  6. Reinders, Mattheus K.; Roon, Eric N.; Houtman, Pieternella M.; Brouwers, Jacobus R. B. J.; Jansen, Tim L. Th. A. (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.
  7. 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.
  8. Reinders, M K; Van Roon, E N; Jansen, T L T. A; Delsing, J; Griep, E N; Hoekstra, M; Van De Laar, M A F J; Brouwers, J R B J (2008). "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.
  9. Hummel, M. A. (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.
  10. Locuson, Charles W.; Rock, Denise A.; Jones, Jeffrey P. (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.
  11. Locuson, Charles W.; Suzuki, Hisashi; Rettie, Allan E.; Jones, Jeffrey P. (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.
  12. Lee, Ming-Han H; Graham, Garry G; Williams, Kenneth M; Day, Richard O (2008). "A Benefit-Risk Assessment of Benzbromarone in the Treatment of Gout". Drug Safety. 31 (8): 643–65. doi:10.2165/00002018-200831080-00002. PMID 18636784.
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