Metabolism of benzbromarone in man

Broekhuysen, J.; Pacco, Michel; Sion, R.; Demeulenaere, L; Hee, M. van

doi:10.1007/bf00562509

Cited by 40 publications

(12 citation statements)

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“…Debromination was initially considered a main bioactivator of BBR in vivo (Broekhuysen et al, 1972;Ferber et al, 1981). It was clarified in 1988 that hydroxylation rather than debromination was the predominant metabolic pathway of BBR (Walter-Sack et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

Identification of Epoxide-Derived Metabolite(s) of Benzbromarone

Wang

Peng

et al. 2016

Drug Metabolism and Disposition

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Benzbromarone (BBR) is a benzofuran derivative that has been quite useful for the treatment of gout; however, it was withdrawn from European markets in 2003 because of reported serious incidents of drug-induced liver injury. BBR-induced hepatotoxicity has been suggested to be associated with the formation of a quinone intermediate. The present study reported epoxide-derived intermediate(s) of BBR. An N-acetylcysteine (NAC) conjugate derived from epoxide metabolite(s) was detected in both microsomal incubations of BBR and urine samples of mice treated with BBR. The NAC conjugate was identified as 6-NAC BBR. Ketoconazole suppressed the bioactivation of BBR to the epoxide intermediate(s), and the CYP3A subfamily was the primary enzyme responsible for the formation of the epoxide(s). The present study provided new information on metabolic activation of BBR.

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Section: Introductionmentioning

confidence: 99%

Identification of Epoxide-Derived Metabolite(s) of Benzbromarone

Wang

Peng

et al. 2016

Drug Metabolism and Disposition

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“…Hepatotoxicity is often associated with cytochrome P450‐mediated bioactivation , and so it may be instructive to consider what is known about the metabolism of BBR. Early metabolic studies revealed two major hydroxylated metabolites, M1 and M2, in urine, bile and plasma . M1 and M2 were identified as 1′‐hydroxy BBR and 6‐hydroxy BBR, respectively .…”

Section: Introductionmentioning

confidence: 99%

Identification of CYP isozymes involved in benzbromarone metabolism in human liver microsomes

Kobayashi

Kajiwara

Ishikawa

et al. 2012

Biopharm & Drug Disp

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Benzbromarone (BBR) is metabolized to 1'-hydroxy BBR and 6-hydroxy BBR in the liver. 6-Hydroxy BBR is further metabolized to 5,6-dihydroxy BBR. The aim of this study was to identify the CYP isozymes involved in the metabolism of BBR to 1'-hydroxy BBR and 6-hydroxy BBR and in the metabolism of 6-hydroxy BBR to 5,6-dihydroxy BBR in human liver microsomes. Among 11 recombinant P450 isozymes examined, CYP3A4 showed the highest formation rate of 1'-hydroxy BBR. The formation rate of 1'-hydroxy BBR significantly correlated with testosterone 6β-hydroxylation activity in a panel of 12 human liver microsomes. The formation of 1'-hydroxy BBR was completely inhibited by ketoconazole in pooled human liver microsomes. On the other hand, the highest formation rate of 6-hydroxy BBR was found in recombinant CYP2C9. The highest correlation was observed between the formation rate of 6-hydroxy BBR and diclofenac 4'-hydroxylation activity in 12 human liver microsomes. The formation of 6-hydroxy BBR was inhibited by tienilic acid in pooled human liver microsomes. The formation of 5,6-dihydroxy BBR from 6-hydroxy BBR was catalysed by recombinant CYP2C9 and CYP1A2. The formation rate of 5,6-dihydroxy BBR was significantly correlated with diclofenac 4'-hydroxylation activity and phenacetin O-deethylation activity in 12 human liver microsomes. The formation of 5,6-dihydroxy BBR was inhibited with either tienilic acid or α-naphthoflavone in human liver microsomes. These results suggest that (i) the formation of 1'-hydroxy BBR and 6-hydroxy BBR is mainly catalysed by CYP3A4 and CYP2C9, respectively, and (ii) the formation of 5,6-dihydroxy BBR is catalysed by CYP2C9 and CYP1A2 in human liver microsomes.

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“…About 60 % of the native molecule is absorbed, and derivatives of bromobenzarone and benzarone are conjugated to glucuronic acid and excreted in the bile (80 %) and urine (20 %). Although the serum half-life of benzbromarone is roughly 12 h, enterohepatic recirculation of its dehalogenated metabolite, benzarone, permits the detection of this metabolite for over 48 h [ 575 ] . The drug is strongly bound to plasma proteins.…”

Section: Benzbromaronementioning

confidence: 99%

Management of Hyperuricemia and Gout

Newcombe¹

2012

Gout

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Metabolism of benzbromarone in man

Cited by 40 publications

References 5 publications

Identification of Epoxide-Derived Metabolite(s) of Benzbromarone

Identification of Epoxide-Derived Metabolite(s) of Benzbromarone

Identification of CYP isozymes involved in benzbromarone metabolism in human liver microsomes

Management of Hyperuricemia and Gout

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