Metabolism and disposition of lesinurad, a uric acid reabsorption inhibitor, in humans. (3rd July 2019)

• Record Type: Journal Article
• Authors: Shah, Vishal; Yang, Chun; Shen, Zancong; Kerr, Bradley M.; Tieu, Kathy; Wilson, David M.; Hall, Jesse; Gillen, Michael; Lee, Caroline A.
• Is Part Of: Xenobiotica. Volume 49:Number 7(2019:Jul.)
• Page Start: 811
• Page End: 822
• Publication Date: 2019-07-03
• Subjects: [14C]lesinurad -- absolute bioavailability -- CYP2C9 -- human -- disposition -- accelerated mass spectrometry (AMS) -- epoxide hydrolase; Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.1080/00498254.2018.1504257
• Languages: English
• ISSNs: 0049-8254

Abstract

Abstract: The objectives of this study were to determine the absolute bioavailability of lesinurad and to characterized its disposition in humans. The oral bioavailability assessment was performed using a clinical design of simultaneous dosing of a therapeutic oral dose of lesinurad with an intravenous infusion of [ 14 C]lesinurad microdose. The bioavailability of lesinurad was determined to be 100%. The disposition of lesinurad in humans involves hepatic oxidation and renal elimination following administration of oral [ 14 C]lesinurad dose. Metabolism of lesinurad occurred post-systemically with low circulating levels of metabolites <3% of total radioactivity as 74.2% of total radioactivity was attributed to lesinurad. In vitro metabolism studies identified CYP2C9 as the predominant isoform, and summation of metabolites indicated that it was responsible for ∼50% of metabolism.