Metabolism of benzbromarone in man: structures of new oxidative metabolites, 6-hydroxy- and 1″-oxo-benzbromarone, and the enantioselective formation and elimination of 1″-hydroxybenzbromarone

Abstract

1. The uricosuric drug benzbromarone is extensively metabolized in man and two main metabolites are formed: the previously characterized 1'-hydroxybenzbromarone (metabolite M1) and an arylhydroxybenzbromarone (metabolite M2) of unknown structure. A dimethyl derivative was isolated from urine after methylation and was characterized by gas chromatography-mass spectrometry (g.l.c.-m.s.) and high resolution nuclear magnetic resonance spectroscopy as 4''-O-methyl-6-methoxybenzbromarone; the structure of M2 therefore is 6-hydroxybenzbromarone. 2. A minor metabolite was similarly characterized as 1'-oxobenzbromarone by comparison with authentic synthetic samples and is a product of biodegradation and not an artifact derived from the in vitro oxidation of 1'-hydroxybenzbromarone. Further minor metabolites were detected and were provisionally characterized by g.l.c.-m.s. after derivatization and include: 2'-hydroxybenzbromarone (an isomer of 1'-hydroxybenzbromarone); 1',6-dihydroxybenzbromarone; dihydroxy-aryl-benzbromarone; and two structure isomers of 6-hydroxybenzbromarone. Debrominated metabolites were not detectable. 3. Benzbromarone is hydroxylated in vivo at the prochiral centre C1' to 1'-hydroxybenzbromarone; analysis of 1'-hydroxybenzbromarone from plasma and urine extracts by h.p.l.c. using a chiral column revealed that two peaks were eluted which showed a mean enantiomeric ratio of 2.1 for plasma and 7.3 for urine; these data demonstrate that the formation and elimination of this metabolite is enantioselective; the absolute configuration of the 1'-chiral centre is presently unknown.

A New Class of Cyp2c9 Inhibitors: Probing 2c9 Specificity With High-Affinity Benzbromarone Derivatives

“…The primary metabolite of Bzbr is also opposite the acidic phenol, occurring at position 6 (Fig. 1) of the benzofuran heterocycle (De Vries et al, 1993). As with the nonsteroidal anti-inflammatory drugs, this places the anion of the molecule near a proposed cationic site on the protein (Jones et al, 1996b) and the metabolized position adjacent to the heme.…”

Identification of Epoxide-Derived Metabolite(s) of Benzbromarone

“…It was clarified in 1988 that hydroxylation rather than debromination was the predominant metabolic pathway of BBR (Walter-Sack et al, 1988). Early metabolic studies revealed two major hydroxylated metabolites identified as 19-hydroxy BBR and 6-hydroxy BBR (De Vries et al, 1993;Walter-Sack et al, 1998). It was also reported that P450s 2C9 (major) and 2C19 (minor) were involved in the formation of the 6-hydroxy BBR metabolite (De Vries et al, 1993), characterized by comparison with synthetic standard (McDonald and Rettie, 2007).…”

“…Early metabolic studies revealed two major hydroxylated metabolites identified as 19-hydroxy BBR and 6-hydroxy BBR (De Vries et al, 1993;Walter-Sack et al, 1998). It was also reported that P450s 2C9 (major) and 2C19 (minor) were involved in the formation of the 6-hydroxy BBR metabolite (De Vries et al, 1993), characterized by comparison with synthetic standard (McDonald and Rettie, 2007). Initially, BBR was found to be a P450 2C9 inhibitor (Marques-Soares et al, 2003;.…”

Joint FAO/WHO Expert Committee on Food Additives (JECFA)

“…Two healthy male volunteers were administered a single oral daily dose of 100 mg benzbromarone [(3,5-dibromo-4-hydroxyphenyl) (2-ethyl-3-benzofuranyl) methanone] for 8 consecutive days (DeVries et al, 1993). The major metabolites were formed by C1 -hydroxylation to yield the corresponding 1 -hydroxybenzbromarone and by hydroxylation of the benzene side-chain to yield 6-hydroxybenzbromarone.…”