Lesinurad as a serum uric acid lowering therapy for chronic gout

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Lesinurad as a serum uric acid lowering therapy for chronic gout

Metabolic disorder causes accumulation of urate crystals, thereby resulting in hyperuricemia (elevated serum uric acid; sUA). Hyperuricemia is characterized by pain and inflammation in joints, soft tissues, and organs is an ill-condition known as gout. Surplus body burden of uric acid promotes gout. Diminished renal clearance of uric acid induces hyperuricemia in most patients with gout, and the renal urate transporter (URAT)1 is critical for regulation of sUA levels. Probenecid and benzbromarone (URAT1 inhibitors) are used as gout therapies; however, their application is restricted by drug–drug interactions and off-target toxicity, respectively.

Miner J N et al coonduccted a study to define the mechanism of action of lesinurad (Zurampic®; RDEA594), a novel URAT1 inhibitor, recently approved in the USA and Europe for chronic gout treatment.

The lesinurad plasma levels, fractional excretion of uric acid (FEUA) and urinary excretion of lesinurad were calculated in healthy volunteers treated with lesinurad. Also, lesinurad, probenecid, and benzbromarone were compared (in vitro setting) for effects on urate transporters and the organic anion transporter 1 (OAT)1 and OAT3, changes in mitochondrial membrane potential, and the activity of human peroxisome proliferator-activated receptor gamma (PPARγ).

As per the results, single 200 mg dose of lesinurad elevated FEUA 3.6-fold (P < 0.001) and reduced sUA levels by 33 % (P < 0.001) after 6 hours. At concentrations attained in the clinic, lesinurad inhibited activity of URAT1 and OAT4 in vitro, did not inhibit GLUT9, and had no effect on ABCG2. Lesinurad also revealed a low risk for mitochondrial toxicity and PPARγ induction compared to benzbromarone. Lesinurad did not inhibit OAT1 or OAT3 in the clinical setting, unlike probenecid.

Hence, the pharmacodynamic effects and in vitro activity of lesinurad are consistent with inhibition of URAT1 and OAT4, vital apical transporters for uric acid. Lesinurad also has a favorable selectivity and safety profile, consistent with a significant function in sUA-lowering therapy for patients with gout.


Arthritis Research & Therapy

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Original title of article:

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


 Jeffrey N. Miner et al.

Arthritis Research & Therapy
Therapeutic, Lesinurad, Probenecid, Benzbromarone, Gout, Joints, URAT1 Inhibitor, Uricosurics, Efficacy, Safety
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