RT Journal Article
SR Electronic
T1 Metabolism and Disposition of Verinurad, a Uric Acid Reabsorption Inhibitor, in Humans
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.117.078220
DO 10.1124/dmd.117.078220
A1 Caroline A. Lee
A1 Chun Yang
A1 Vishal Shah
A1 Zancong Shen
A1 David M Wilson
A1 Traci M. Ostertag
A1 Jesse Hall
A1 Jean-Luc Girardet
A1 Michael Gillen
YR 2018
UL http://dmd.aspetjournals.org/content/early/2018/02/28/dmd.117.078220.abstract
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.