Metabolism and excretion of [14C] febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase, in healthy male subjects.
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.
Grabowski
Brian A
BA
Takeda Global Research and Development Center, Inc, 675 North Field Drive, Lake Forest, IL 60045, USA. brian.grabowski@tgrd.com
Khosravan
Reza
R
Vernillet
Laurent
L
Mulford
Darcy J
DJ
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D000069465:Febuxostat; D006074:Gout Suppressants / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013844:Thiazoles / Q000493:pharmacokinetics*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*; D055815:Young Adult
D006074:Gout Suppressants; D013844:Thiazoles; D000069465:Febuxostat; D014969:Xanthine Oxidase