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.
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.
De Vries
J X
JX
Department of Medicine, University of Heidelberg, Germany.
Walter-Sack
I
I
Voss
A
A
Forster
W
W
Ilisistegui Pons
P
P
Stoetzer
F
F
Spraul
M
M
Ackermann
M
M
Moyna
G
G
D000328:Adult; D001553:Benzbromarone / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D013237:Stereoisomerism
C086341:1'-oxobenzbromarone; C085923:6-hydroxybenzbromarone; C085922:1'-hydroxybenzbromarone; D001553:Benzbromarone