title: Lesinurad, a novel, oral compound for gout, acts to decrease serum uric acid through inhibition of urate transporters in the kidney.
abstract: 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.
  
  
  
  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.
  
  
  
  After 6 hours, a single 200-mg dose of lesinurad elevated FEUA3.6-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.
  
  
  
  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.
authors.affiliation: Ardea Biosciences, Inc., 9390 Towne Centre Drive, San Diego, CA, 92121, USA. jminer@ardeabio.com.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Miner
authors.affiliation: Ardea Biosciences, Inc., 9390 Towne Centre Drive, San Diego, CA, 92121, USA.
authors.forename: Philip K
authors.initials: PK
authors.lastname: Tan
authors.affiliation: Ardea Biosciences, Inc., 9390 Towne Centre Drive, San Diego, CA, 92121, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hyndman
authors.affiliation: Ardea Biosciences, Inc., 9390 Towne Centre Drive, San Diego, CA, 92121, USA.
authors.forename: Sha
authors.initials: S
authors.lastname: Liu
authors.affiliation: Ardea Biosciences, Inc., 9390 Towne Centre Drive, San Diego, CA, 92121, USA.
authors.forename: Cory
authors.initials: C
authors.lastname: Iverson
authors.affiliation: Ardea Biosciences, Inc., 9390 Towne Centre Drive, San Diego, CA, 92121, USA.
authors.forename: Payal
authors.initials: P
authors.lastname: Nanavati
authors.affiliation: Ardea Biosciences, Inc., 9390 Towne Centre Drive, San Diego, CA, 92121, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Hagerty
authors.affiliation: Ardea Biosciences, Inc., 9390 Towne Centre Drive, San Diego, CA, 92121, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Manhard
authors.affiliation: Ardea Biosciences, Inc., 9390 Towne Centre Drive, San Diego, CA, 92121, USA.
authors.forename: Zancong
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Ardea Biosciences, Inc., 9390 Towne Centre Drive, San Diego, CA, 92121, USA.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Girardet
authors.affiliation: Ardea Biosciences, Inc., 9390 Towne Centre Drive, San Diego, CA, 92121, USA.
authors.forename: Li-Tain
authors.initials: LT
authors.lastname: Yeh
authors.affiliation: University of California San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Terkeltaub
authors.affiliation: Ardea Biosciences, Inc., 9390 Towne Centre Drive, San Diego, CA, 92121, USA.
authors.forename: Barry
authors.initials: B
authors.lastname: Quart
mesh_terms: D002460:Cell Line; D006073:Gout; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008297:Male; D027361:Organic Anion Transporters / Q000187:drug effects*; D027701:Organic Cation Transport Proteins / Q000187:drug effects*; D013864:Thioglycolates / Q000493:pharmacokinetics*; D014230:Triazoles / Q000493:pharmacokinetics*; D014527:Uric Acid / Q000097:blood*; D014528:Uricosuric Agents / Q000493:pharmacokinetics*
chemical_list: D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; D013864:Thioglycolates; D014230:Triazoles; D014528:Uricosuric Agents; C000593471:lesinurad; D014527:Uric Acid
keywords: Gout; RDEA594; URAT1; Uric Acid