METABOLISM OF BENZBROMARONE IN MAN - STRUCTURES OF NEW OXIDATIVE METABOLITES, 6-HYDROXY-BENZBROMARONE AND 1'-OXO-BENZBROMARONE, AND THE ENANTIOSELECTIVE FORMATION AND ELIMINATION OF 1'-HYDROXYBENZBROMARONE

1. The uricosuric drug benzbromarone is extensively metabolized in man and two main metabolites are formed: the previously characterized 1'- hydroxybenzbromarone (metabolite MI) and an arylhydroxybenzbromarone ( metabolite M2) of unknown structure. A dimethyl derivative was isolate d from urine after methylation and was characterized by gas chromatogr aphy-mass spectrometry (g.l.c.-m.s.) and high resolution nuclear magne tic resonance spectroscopy as 4''-O-methyl-6-methoxybenzbromarone; the structure of M2 therefore is 6-hydroxybenzbromarone. 2. A minor metab olite was similarly characterized as 1'-oxobenzbromarone by comparison with authentic synthetic samples and is a product of biodegradation a nd not an artifact derived from the in vitro oxidation of 1'-hydroxybe nzbromarone. Further minor metabolites were detected and were provisio nally characterized by g.l.c.-m.s. after derivatization and include: 2 '-hydroxybenzbromarone (an isomer of 1'-hydroxybenzbromarone); 1,6-dih ydroxybenzbromarone; dihydroxy-aryl-benzbromarone; and two structure i somers of 6-hydroxybenzbromarone. Debrominated metabolites were not de tectable. 3. Benzbromarone is hydroxylated in vivo at the prochiral ce ntre Cl' to 1'-hydroxybenzbromarone; analysis of 1'-hydroxybenzbromaro ne from plasma and urine extracts by h.p.l.c. using a chiral column re vealed that two peaks were eluted which showed a mean enantiomeric rat io of 2.1 for plasma and 7.3 for urine; these data demonstrate that th e formation and elimination of this metabolite is enantioselective; th e absolute configuration of the 1'-chiral centre is presently unknown.