Overview of uricosurics: past, present, and future

Time periodAgentClinical experience to dateMechanism of actionKey safety signals
PastProbenecid [6, 21, 34, 41, 42, 109]

  • Developed in 1949;

  • US approved in 1951;

  • Approved for the treatment of hyperuricemia associated with gout and gouty arthritis;

  • Usage declined during the 1960s, although still approved in the US, Europe, and Japan.

Non-specific: inhibits anion transporters URAT1, OAT1, OAT3, and GLUT9

  • Nephrolithiasis;

  • Drug-drug interactions.

Benzbromarone [6, 21, 36, 110]

  • In use since the early 1970s for the treatment of hyperuricemia associated with gout;

  • Approved in Europe and Japan, but never received FDA approval;

  • Removed from European market in 2003 amid reports of severe hepatotoxicity.

Non-specific: acts mainly on URAT1, but also on OAT1, OAT3, and GLUT9

  • Severe rare hepatotoxicity;

  • GI intolerance;

  • Allergic reaction (skin rash, conjunctivitis);

  • Nephrolithiasis.

Sulfinpyrazone [6, 7, 21, 39, 43, 111]

  • FDA approved in 1959 for the treatment of hyperuricemia associated with gouty arthritis;

  • Widely discontinued by manufacturer, although still available in Japan and Thailand.

Thought to inhibit URAT1 and MRP4

  • Acute renal injury;

  • Platelet aggregation impairment;

  • Rare bone marrow toxicity;

  • Skin rashes;

  • GI intolerance.

Phenylbutazone [21, 112, 113]

  • First approved in 1952, initially for the treatment of rheumatoid arthritis and gout;

  • Withdrawn from use in humans in the 1980s due to safety concerns, but still widely used in equine medicine;

  • Indicated for ankylosing spondylitis where other therapies are unsuitable.

NSAID, small study demonstrated mild uricosuric propertiesBlood dyscrasias
Zoxazolamine [21]

  • FDA approved in 1956 for the treatment of skeletal muscle spasms but used only for a two-year period;

  • Also a potent uricosuric with rapid onset.

Muscle relaxant (calcium channel blocker)Fatal hepatotoxicity
Benziodarone [21, 49]

  • Medication with antimicrobial/antitumor/antiviral and urate-lowering activity;

  • Withdrawn in 1964.

VasodilatorJaundice
PresentLesinurad [6, 17, 21, 38, 55, 57]

  • US approved in 2015 for treatment of hyperuricemia associated with gout as combination therapy with a XOI (with a boxed warning regarding acute renal failure);

  • Both lesinurad tablet and lesinurad + allopurinol fixed-dose combination were withdrawn by manufacturer in 2019, for commercial reasons unrelated to safety or efficacy.

URAT1, OAT1, OAT3, and OAT4 inhibitorRaised creatinine and nephrolithiasis when used as monotherapy
Verinurad (RDEA3170) [6, 21, 65, 66]

  • Investigational: not yet approved;

  • Six phase 2 trials complete (NCT03316131, NCT02078219, NCT02317861, NCT02246673, NCT01927198, NCT02498652)*;

  • No phase 3 trials have been registered to date.

Selective URAT1 inhibitorRenal-related adverse events and elevated creatinine were common in clinical trials
Dotinurad [21, 71]

  • Approved in Japan in 2020;

  • Studied in patients with hyperuricemia with or without gout.

Selective URAT1 inhibitor

  • No renal or hepatic safety signals;

  • No specific safety concerns have been identified in clinical studies.

FutureRuzinurad (SHR4640) [73, 74]

  • Investigational: not yet approved;

  • Three phase 2 trials (NCT03185793, NCT04180982, NCT05513976) are complete or are underway;

  • Two phase 3 trials ongoing in China (NCT04052932, NCT04956432).

Selective URAT1 inhibitorNo serious hepatic or safety signals have been observed [76, 77]; yet acute kidney injury has occurred rarely in clinical trials [77]
Pozdeutinurad (AR882) [75, 77, 78]

  • Investigational: not yet approved;

  • Two phase 2 trials complete (NCT04155918, NCT05119686);

  • One phase 2 trial (NCT05253833) is ongoing extension studies;

  • One phase 3 trial (NCT06439602) is ongoing.

Selective URAT1 inhibitor; optimized from benzbromarone metabolite scaffoldNo serious adverse events and no renal or hepatic safety signals have been reported in clinical trials
Epaminurad (URC102/UR-1102) [40, 79]

  • Investigational: not yet approved, although investigational new drug applications submitted in Malaysia and South Korea;

  • Three phase 2 trials (NCT02290210, NCT04804111, NCT02557126) completed in Korean patients;

  • One phase 3 trial (NCT05815901) is recruiting.

URAT1 inhibitor; derived from benzbromaroneNo serious adverse events have been reported in clinical trials
ABP-671 [82]

  • Investigational: not yet approved;

  • One phase 2a trial (NCT04638543) complete;

  • Two phase 2b/3 trials (NCT06276556, NCT05818085) are ongoing.

URAT1 inhibitorNephrolithiasis reported in clinical trials
Xininurad (XNW-3009)

  • Investigational: not yet approved;

  • One phase 2/3 trial (CTR20222360) is ongoing in China.

URAT1 inhibitorNo trial data are yet available

* Only trials in the indications of gout or hyperuricemia are listed. FDA: US Food and Drug Administration; GI: gastrointestinal; GLUT9: glucose transporter 9; MRP4: multidrug resistance protein 4; NSAID: nonsteroidal anti-inflammatory drug; OAT1: organic ion transporter 1; URAT1: urate transporter 1; XOI: xanthine oxidase inhibitor