PT  - JOURNAL ARTICLE
AU  - Caroline A. Lee
AU  - Chun Yang
AU  - Vishal Shah
AU  - Zancong Shen
AU  - David M Wilson
AU  - Traci M. Ostertag
AU  - Jesse Hall
AU  - Jean-Luc Girardet
AU  - Michael Gillen
TI  - Metabolism and Disposition of Verinurad, a Uric Acid Reabsorption Inhibitor, in Humans
AID  - 10.1124/dmd.117.078220
DP  - 2018 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.117.078220
4099  - http://dmd.aspetjournals.org/content/early/2018/02/28/dmd.117.078220.short
4100  - http://dmd.aspetjournals.org/content/early/2018/02/28/dmd.117.078220.full
AB  - Following a single oral solution of 10 mg dose of [14C]verinurad (500 μCi), verinurad was rapidly absorbed with a median Tmax of 0.5 hour and terminal half-life of 15 hours. In human plasma, verinurad constituted 21% of total radioactivity. The majority of circulating radioactivity is associated with plasma with no preferential distribution of the drug to red blood cells. Recovery of radioactivity in urine and feces was 97.1%. Unchanged verinurad was the predominant component in the feces (29.9%) while levels were low in the urine (1.2% excreted). Acylglucuronide metabolites M1 (direct glucuronidation) and M8 (glucuronidation of N-oxide) formed rapidly after absorption of verinurad with terminal half-lives of approximately 13 and 18 hours, respectively. M1 and M8 constituted 32% and 31% of total radioactivity in plasma and equimolar to verinurad based on AUC ratios. M1 and M8 accounted for 29.2% and 32.5% of the radioactive dose in urine, respectively, with none detected in the feces. The N-oxide metabolite (M4) was formed by CYP3A4 and underwent rapid sequential metabolism by glucuronyl transferases (UGTs) to form M8 as M4 was not detected in the plasma, but trace levels were recovered in the urine (<1%). M1 formation was mediated by several UGTs and can be further metabolized by CYP2C8 to form M8.