Benzbromarone hydroxylation in man: defective formation of the 6-hydroxybenzbromarone metabolite

Abstract

To determine the elimination phenotype of the uricosuric agent benzbromarone 100 mg of the drug was administered as a single oral dose to 11 volunteers on a formula diet; plasma concentration-time profiles of the parent drug and the main metabolites M 1 (l'-hydroxybenzbromarone) and M 2 (6-hydroxy-benzbromarone) were measured by high-performance liquid chromatography for 168 h. Of the 11 subjects 2 showed higher plasma concentrations and delayed elimination of benzbromarone and metabolite M1 but reduced formation of metabolite M 2 compared to the other 9 subjects. However, the plasma concentration-time profiles of the metabolites in these two slow eliminators, termed type 2, differed from those of a poor eliminator characterized during a previous study; the latter, termed type 1, eliminated benzbromarone as well as both metabolites M~ and M 2 slowly. The differences in the elimination of benzbromarone and its metabolites are probably caused by differences in the activities of the cytochrome P45o mono-oxygenase isozymes. The results show that determination of the phenotype solely by measurement of the 24-h benzbromarone plasma concentration does not unequivocally characterize slow benzbromarone eliminators; additional plasma concentration-time profiles of the parent drug and metabolites are necessary. Metabolite M 2 is characterized as 6-hydroxybenzbromarone; the formation and elimination of the chiral metabolite M 1 is enantioselective.

Benzbromarone in the treatment of gout

“…Benzbromarone has a hepatic metabolism, mainly through cytochrome P450 2C9 (CYP2C9). Its primary metabolites are 6-hydroxybenzbromarone, which is related to its uricosuric effect, and 1′-hydroxybenzbromarone, whose uricosuric effect is unknown [17]. The intact drug's half-life is approximately 3 h; however, its active metabolite can persist for 30 h, resulting in a prolonged effect [18].…”

Structure-Activity Relationships of Benzbromarone Metabolites and Derivatives as EYA Inhibitory Anti-Angiogenic Agents

“…6OH-BBR was the most potent inhibitor of cell migration, tube formation and aortic ring sprouting tested here. 6OH-BBR is a major metabolite of BBR and has a much longer half-life (30 hours relative to 3 hours for BBR as previously reported [ 24 , 29 ]) raising the interesting possibility that, in the context of angiogenesis, BBR may act as a pro-drug with biotransformation into 6OH-BBR yielding a pharmacologically active metabolite. It also suggests that polar substituents at position 6 of the benzofuran would yield more effective anti-angiogenic agents.…”

“…The hydroxylated BBR metabolites 6OH-BBR and 1’-hydroxybenzbromarone (1’OH-BBR) ( Figure 1A ) are detected in plasma, bile and urine after oral administration [ 24 ]; 6OH-BBR is primarily the consequence of CYP2C9 – mediated metabolism, while 1’OH-BBR is the product of CYP3A4-mediated metabolism. Other proposed minor metabolites of BBR include 5OH-BBR ( Figure 1A ) and catechols derived from di-hydroxylation of the aryl ring of the benzofuran [ 17 , 18 ].…”

Metabolism studies of benzbromarone in rats by high performance liquid chromatography–quadrupole time of flight mass spectrometry

“…In addition, they pointed out that glucuronide conjugates were the major phase II metabolites with enzymatic hydrolysis method. In 1990s, many people held that the biotransformation of BBR varied in humans through a population study and that the toxicity of BBR might be a familial disorder [10][11][12][13][14]. The only data available Abbreviations:…”