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Metabolism and Excretion of [ 14 C] Febuxostat, a Novel Nonpurine Selective Inhibitor of Xanthine Oxidase, in Healthy Male Subjects
Author(s) -
Grabowski Brian A.,
Khosravan Reza,
Vernillet Laurent,
Mulford Darcy J.
Publication year - 2011
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270010365549
Subject(s) - febuxostat , xanthine oxidase , metabolism , excretion , endocrinology , pharmacology , medicine , chemistry , xanthine oxidase inhibitor , uric acid , urine , hyperuricemia , enzyme , biochemistry
Absorption, metabolism, and excretion of one 80 mg oral dose of [ 14 C] febuxostat ([thiazole‐4‐ 14 C] 2‐[3‐cyano‐4‐isobutoxyphenyl]‐4‐methyl‐5‐thiazolecarboxylic acid) were studied in 6 healthy subjects. Mean cumulative recovery in excreta was 94% (49% urine and 45% feces) of the dose over 9 days; 87% of the dose was profiled. Seventeen radioactive peaks were observed in urine and fecal chromatograms. Unchanged febuxostat contributed to a combined total in excreta of 10% to 18% of the dose, indicating that it was extensively metabolized and well absorbed. Metabolites were 67M‐1 (10%) and 67M‐2 (11%) hydroxylated febuxostat, febuxostat acyl‐glucuronide (30%), 67M‐4 di‐carboxylic acid (14%), 67M‐1 sulfate conjugate (3%), and dehydrated 67M‐1/67M‐2 acyl‐glucuronide (0.5%). Febuxostat and these metabolites accounted for 82% of profiled dose; unidentified peaks individually contributed <1.3% of the dose. Febuxostat and total radioactivity plasma C max values were observed at 0.5 hour postdose, suggesting that febuxostat was quickly absorbed. At 4 hours postdose, plasma chromatographic profiles contained 6 peaks: febuxostat (85%), 67M‐1 (4%), 67M‐2 (5%), febuxostat acyl‐glucuronide (4%), 67M‐4 (1%), and 67M‐1 sulfate (0.5%). Compared to total radioactivity, febuxostat accounted for 94% at C max and 83% of the area under the concentration‐time curve (AUC) values. Based on the whole blood to plasma total radioactivity, little radioactivity was associated with red blood cells.