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

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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 (FE UA), 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 FE UA 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.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13075-016-1107-x) contains supplementary material, which is available to authorized users.

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          Molecular identification of a renal urate anion exchanger that regulates blood urate levels.

          Atsushi Enomoto, Hiroaki Kimura, Arthit Chairoungdua … (2002)
          Urate, a naturally occurring product of purine metabolism, is a scavenger of biological oxidants implicated in numerous disease processes, as demonstrated by its capacity of neuroprotection. It is present at higher levels in human blood (200 500 microM) than in other mammals, because humans have an effective renal urate reabsorption system, despite their evolutionary loss of hepatic uricase by mutational silencing. The molecular basis for urate handling in the human kidney remains unclear because of difficulties in understanding diverse urate transport systems and species differences. Here we identify the long-hypothesized urate transporter in the human kidney (URAT1, encoded by SLC22A12), a urate anion exchanger regulating blood urate levels and targeted by uricosuric and antiuricosuric agents (which affect excretion of uric acid). Moreover, we provide evidence that patients with idiopathic renal hypouricaemia (lack of blood uric acid) have defects in SLC22A12. Identification of URAT1 should provide insights into the nature of urate homeostasis, as well as lead to the development of better agents against hyperuricaemia, a disadvantage concomitant with human evolution.
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            SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout.

            Veronique Vitart, Igor Rudan, Caroline Hayward … (2008)
            Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200-500 microM) compared with other mammals (3-120 microM). About 70% of daily urate disposal occurs via the kidneys, and in 5-25% of the human population, impaired renal excretion leads to hyperuricemia. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7-5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes.
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              Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study.

              Abbas Dehghan, Anna Köttgen, Qiong Yang … (2008)
              Hyperuricaemia, a highly heritable trait, is a key risk factor for gout. We aimed to identify novel genes associated with serum uric acid concentration and gout. Genome-wide association studies were done for serum uric acid in 7699 participants in the Framingham cohort and in 4148 participants in the Rotterdam cohort. Genome-wide significant single nucleotide polymorphisms (SNPs) were replicated in white (n=11 024) and black (n=3843) individuals who took part in the study of Atherosclerosis Risk in Communities (ARIC). The SNPs that reached genome-wide significant association with uric acid in either the Framingham cohort (p<5.0 x 10(-8)) or the Rotterdam cohort (p<1.0 x 10(-7)) were evaluated with gout. The results obtained in white participants were combined using meta-analysis. Three loci in the Framingham cohort and two in the Rotterdam cohort showed genome-wide association with uric acid. Top SNPs in each locus were: missense rs16890979 in SLC2A9 (p=7.0 x 10(-168) and 2.9 x 10(-18) for white and black participants, respectively); missense rs2231142 in ABCG2 (p=2.5 x 10(-60) and 9.8 x 10(-4)), and rs1165205 in SLC17A3 (p=3.3 x 10(-26) and 0.33). All SNPs were direction-consistent with gout in white participants: rs16890979 (OR 0.59 per T allele, 95% CI 0.52-0.68, p=7.0 x 10(-14)), rs2231142 (1.74, 1.51-1.99, p=3.3 x 10(-15)), and rs1165205 (0.85, 0.77-0.94, p=0.002). In black participants of the ARIC study, rs2231142 was direction-consistent with gout (1.71, 1.06-2.77, p=0.028). An additive genetic risk score of high-risk alleles at the three loci showed graded associations with uric acid (272-351 mumol/L in the Framingham cohort, 269-386 mumol/L in the Rotterdam cohort, and 303-426 mumol/L in white participants of the ARIC study) and gout (frequency 2-13% in the Framingham cohort, 2-8% in the Rotterdam cohort, and 1-18% in white participants in the ARIC study). We identified three genetic loci associated with uric acid concentration and gout. A score based on genes with a putative role in renal urate handling showed a substantial risk for gout.
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                Author and article information

                Contributors
                Jeffrey Miner: 858-652-6591 , jminer@ardeabio.com
                Journal
                Journal ID (nlm-ta): Arthritis Res Ther
                Journal ID (iso-abbrev): Arthritis Res. Ther
                Title: Arthritis Research & Therapy
                Publisher: BioMed Central (London )
                ISSN (Print): 1478-6354
                ISSN (Electronic): 1478-6362
                Publication date (Electronic): 3 October 2016
                Publication date PMC-release: 3 October 2016
                Publication date (Print): 2016
                Volume: 18
                Electronic Location Identifier: 214
                Affiliations
                [1 ]Ardea Biosciences, Inc., 9390 Towne Centre Drive, San Diego, CA 92121 USA
                [2 ]University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093 USA
                Article
                Publisher ID: 1107
                DOI: 10.1186/s13075-016-1107-x
                PMC ID: 5048659
                PubMed ID: 27716403
                SO-VID: 2d53f9a8-1418-4a12-a54c-52ca19565963
                Copyright © © The Author(s). 2016
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 4 May 2016
                Date accepted : 2 September 2016
                Funding
                Funded by: Ardea Biosciences, Inc., San Diego, CA, a wholly owned subsidiary of AstraZeneca PLC
                Categories
                Subject: Research Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2016

                ScienceOpen disciplines: Orthopedics
                Keywords: gout,rdea594,uric acid,urat1
                Data availability:
                ScienceOpen disciplines: Orthopedics
                Keywords: gout, rdea594, uric acid, urat1

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