Benzbromarone hydroxylation in man: defective formation of the 6-hydroxybenzbromarone metabolite

To determine the elimination phenotype of the uricosuric agent benzbromarone 100 mg of the drug was administered as a single oral dose to 11 volunteers on a formula diet; plasma concentration-time profiles of the parent drug and the main metabolites M1 (1'-hydroxybenzbromarone) and M2 (6-hydroxy-benzbromarone) were measured by high-performance liquid chromatography for 168 h. Of the 11 subjects 2 showed higher plasma concentrations and delayed elimination of benzbromarone and metabolite M1 but reduced formation of metabolite M2 compared to the other 9 subjects. However, the plasma concentration-time profiles of the metabolites in these two slow eliminators, termed type 2, differed from those of a poor eliminator characterized during a previous study; the latter, termed type 1, eliminated benzbromarone as well as both metabolites M1 and M2 slowly. The differences in the elimination of benzbromarone and its metabolites are probably caused by differences in the activities of the cytochrome P450 mono-oxygenase isozymes. The results show that determination of the phenotype solely by measurement of the 24-h benzbromarone plasma concentration does not unequivocally characterize slow benzbromarone eliminators; additional plasma concentration-time profiles of the parent drug and metabolites are necessary. Metabolite M2 is characterized as 6-hydroxybenzbromarone; the formation and elimination of the chiral metabolite M1 is enantioselective.