Rapid and slow benzbromarone elimination phenotypes in man: benzbromarone and metabolite profiles

Abstract

Following oral administration of the uricosuric drug benzbromarone two major metabolites appear in the circulation. 1'-hydroxy-benzbromarone (M1), and a second product (M2) of unknown structure. The plasma concentrations of the parent drug and of M1 and M2 have now been compared in two different elimination phenotypes. 10 subjects who eliminated the drug rapidly (S1-10) and one individual (S11) whose elimination capacity was impaired, presumably due to genetic variation (S11). The AUC (0-96) of the parent drug in S11 was 145 micrograms.ml-1 h. and in the other individuals it averaged 18.3 (11.4-24.5) micrograms.ml-1 h. The plasma elimination half life of benzbromarone was 3.34 (1.77-5.24) h in the rapid eliminators, and 13.08 h in the subject with the elimination defect. The mean plasma elimination half life of the metabolites in S1-10 amounted to 20.1 (11.9-41.2) h for M1, and 17.2 (12.9-30.7) h for M2. In S11 the plasma elimination half life of M1 was prolonged to 76.6 h, and of M2 to 75.4 h. Thus, the elimination defect in S11 was not restricted to the parent drug, but it also involved the two major metabolites M1 and M2. This might be a consequence of a hepatic enzyme deficiency, or be due to impairment of drug excretion.

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

“…la), resulting in larger AUC0_o~ (Table 2) and longer plasma elimination half-lives than the average of the other subjects (Table 2). , Cma x, rmax, and tl/2 showed greater interindividual variability than the data from the previous elimination phenotype study [21]. This could be due to altered drug disposition of the parent drug in subjects on the formula diet compared to the previous normal diet conditions, for instance, because of diet-related differences of gastrointestinal motility.…”

“…The metabolism of the uricosuric drug benzbromarone (Bzbr) in man has been reinvestigated reAbbreviations: Bzbr = benzbromarone; HPLC = high-performance liquid chromatography * Dedicated to Prof. Dr. G. Paumgartner on the occasion of his 60th birthday cently [1,3,4,15,19,20,21]; instead of the previously reported debrominated compounds bromobenzarone and benzarone [2,8,11,18,23] two main hydroxylated metabolites were detected in plasma and urine samples of volunteers after single oral drug administration. The metabolites M~ and M 2 are characterized as l'-hydroxybenzbromarone and 6-hydroxybenzbromarone respectively [4,6].…”

“…In our previous elimination phenotype study [21] plasma concentration-time profiles of Bzbr in one volunteer differed greatly from the ten others in that the elimination of the main drug and both metabolites M 1 and M 2 was slower than in the rest of the group.…”

“…Thus the 24-h Bzbr concentration alone [13] does not unequivocally classify slow Bzbr eliminators; plasma concentration-time profiles of the parent drug are required to confirm this. The data of the present subjects 2 and 6, which we term type 2 slow eliminator, were compared to those of the poor Bzbr eliminator from the previous phenotype study [21], which we termed as type 1. Slow eliminators of both types eliminate Bzbr slowly but exhibit differences in metabolite formation and elimination.…”

Management of Hyperuricemia and Gout

“…The drug is strongly bound to plasma proteins. A variety of benzbromarone metabolites have been isolated from the urine and their structure characterized [576][577][578][579] .…”