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.