Lesinurad, a novel, oral compound for gout, acts to decrease serum uric acid through inhibition of urate transporters in the kidney

作者：Jeffrey N. Miner, Philip K. Tan, David Hyndman, Sha Liu, Cory Iverson, Payal Nanavati, David Hagerty, Kimberly J. Manhard, Zancong Shen, Jean‐Luc Girardet, Li‐Tain Yeh, Robert Terkeltaub, Barry Quart · 发表于：Arthritis Research & Therapy · 年份：2016 · DOI：10.1186/s13075-016-1107-x · 被引用次数：124 · 研究领域：Gout, Hyperuricemia, Uric Acid、Thyroid Disorders and Treatments、Diet, Metabolism, and Disease

BACKGROUND: Excess body burden of uric acid promotes gout. Diminished renal clearance of uric acid causes hyperuricemia in most patients with gout, and the renal urate transporter (URAT)1 is important for regulation of serum uric acid (sUA) levels. The URAT1 inhibitors probenecid and benzbromarone are used as gout therapies; however, their use is limited by drug-drug interactions and off-target toxicity, respectively. Here, we define the mechanism of action of lesinurad (Zurampic®; RDEA594), a novel URAT1 inhibitor, recently approved in the USA and Europe for treatment of chronic gout. METHODS: ), lesinurad plasma levels, and urinary excretion of lesinurad were measured in healthy volunteers treated with lesinurad. In addition, lesinurad, probenecid, and benzbromarone were compared in vitro for effects on urate transporters and the organic anion transporters (OAT)1 and OAT3, changes in mitochondrial membrane potential, and human peroxisome proliferator-activated receptor gamma (PPARγ) activity. RESULTS: 3.6-fold (p < 0.001) and reduced sUA levels by 33 % (p < 0.001). At concentrations achieved in the clinic, lesinurad inhibited activity of URAT1 and OAT4 in vitro, did not inhibit GLUT9, and had no effect on ABCG2. Lesinurad also showed a low risk for mitochondrial toxicity and PPARγ induction compared to benzbromarone. Unlike probenecid, lesinurad did not inhibit OAT1 or OAT3 in the clinical setting. CONCLUSION: The pharmacodynamic effects and in vitro activity of lesinurad a...