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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2016

Open Access 01-12-2016 | Research article

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

Authors: Jeffrey N. Miner, Philip K. Tan, David Hyndman, Sha Liu, Cory Iverson, Payal Nanavati, David T. Hagerty, Kimberly Manhard, Zancong Shen, Jean-Luc Girardet, Li-Tain Yeh, Robert Terkeltaub, Barry Quart

Published in: Arthritis Research & Therapy | Issue 1/2016

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Abstract

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

sUA levels, fractional excretion of uric acid (FEUA), 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

After 6 hours, a single 200-mg dose of lesinurad elevated FEUA 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 are consistent with inhibition of URAT1 and OAT4, major apical transporters for uric acid. Lesinurad also has a favorable selectivity and safety profile, consistent with an important role in sUA-lowering therapy for patients with gout.
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Metadata
Title
Lesinurad, a novel, oral compound for gout, acts to decrease serum uric acid through inhibition of urate transporters in the kidney
Authors
Jeffrey N. Miner
Philip K. Tan
David Hyndman
Sha Liu
Cory Iverson
Payal Nanavati
David T. Hagerty
Kimberly Manhard
Zancong Shen
Jean-Luc Girardet
Li-Tain Yeh
Robert Terkeltaub
Barry Quart
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2016
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-016-1107-x

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