Part 3 · Lowering urate
How urate-lowering drugs work
There are three ways to lower urate: make less of it, pass more of it out, or break it down. Press play to follow urate from purines to the blood and out through the kidney and gut, then pick a drug to light up the step it blocks.
Schematic. Dots are urate (gold), its precursors (muted) and allantoin (indigo); they are not to scale. The gauge applies the average change reported in one study of each drug to an illustrative starting urate of 8.5 mg/dL [about 506 µmol/L]. The studies differ in people, doses and timing, so the bars are not a head-to-head comparison.
Where urate goes. Xanthine oxidoreductase makes urate in two steps, hypoxanthine to xanthine and xanthine to uric acid. Humans have no working uricase, so urate is the end of the line. 39,297 About two thirds is excreted by the kidney and one third by the gut, and at least 90% of the urate filtered by the kidney is reabsorbed. 39,302 Most people with gout under-excrete urate through the kidney. 313,372
Which route first. ACR 2020 strongly recommends allopurinol as the first-line drug, including in CKD stage ≥3. It strongly prefers allopurinol or febuxostat over probenecid in CKD stage ≥3. It recommends pegloticase only when the other drugs have failed and flares or tophi persist, and strongly recommends against it as a first-line drug. 135
The drugs side by side
| Drug | How it lowers urate | Half-life | Given | Approval and status |
|---|---|---|---|---|
| Allopurinol | Xanthine oxidase inhibitor; purine (hypoxanthine) analogue; active metabolite oxypurinol 87,129 | 1.2 h; oxypurinol 23.3 h, cleared by the kidney 87 | Tablet, once daily 129 | US 19 Aug 1966 (Zyloprim) 100 |
| Febuxostat | Non-purine selective xanthine oxidase inhibitor 18,431 | About 5–8 h 127 | Tablet, once daily 127 | EU 21 Apr 2008; US 13 Feb 2009; US boxed warning for cardiovascular death 2019 100,107,127 |
| Probenecid | Uricosuric: more uric acid excreted in urine 126 | Not quoted in our sources | Tablet, twice daily 126 | Current US generic label; "may not be effective" at GFR ≤30 mL/min 126 |
| Benzbromarone | Uricosuric 225,311 | Not quoted; metabolised by CYP2C9 225 | Tablet, 100 mg/day in the trial quoted here 311 | Withdrawn by Sanofi-Synthélabo in 2003 for liver toxicity, still sold by others; never approved in the US 100,225 |
| Dotinurad | Selective URAT1 inhibitor 396 | Not quoted in our sources | Tablet, 2–4 mg in trials 170,387 | Japan, January 2020 (URECE); US and European phase 3 trials recruiting 283,396 |
| Lesinurad | URAT1 inhibitor, only with a xanthine oxidase inhibitor 128 | Not quoted in our sources | Tablet, 200 mg/day 128 | US 22 Dec 2015, later discontinued; EU withdrawal notified 31 Jul 2020 100,111 |
| Pegloticase | PEGylated recombinant uricase: urate to allantoin 122 | Shortened by anti-drug antibodies 233 | IV infusion every 2 weeks, with methotrexate 122 | US 14 Sep 2010; EU authorised 2013, withdrawn 30 Jun 2016 100,110 |
| Losartan · fenofibrate · SGLT2 inhibitors | Mild urate lowering as a side effect of a drug given for something else 130,435,453 | Not licensed for gout. ACR 2020 conditionally favours losartan for blood pressure when feasible and conditionally recommends against adding or switching to fenofibrate. 135 | ||
Why allopurinol depends on the kidney
23.3 hOxypurinol, the metabolite that does most of the work, has a half-life of 23.3 ± 6.0 h with normal kidney function and is cleared almost entirely in urine. 87 Its clearance falls with creatinine clearance, which is why kidney disease raises exposure. Hande 1984 turned that into creatinine-clearance-based dosing after 78 cases of a severe toxicity syndrome. 154
Later trials raised the dose above that cap to reach target, including in renal impairment. 378,382 See Treat to target.
The enzyme humans lost
Most mammals have uricase, which turns urate into allantoin, about 100 times more soluble. 39,372 In humans, chimpanzees and orangutans a shared nonsense mutation silenced the gene, and gibbons lost it separately. 297,434 Resurrected ancestral enzymes show activity falling steadily along the primate line before the gene was switched off. 219
Pegloticase puts a version of that enzyme back, by infusion. 122
When drug treatment starts
- ACR 2020 strongly recommends urate-lowering therapy with ≥1 tophus, radiographic damage from gout, or ≥2 flares a year. 135
- It conditionally recommends against it after a first flare, unless that flare comes with CKD stage ≥3, serum urate >9 mg/dL [>535 µmol/L] or kidney stones. 135
- It conditionally recommends against drugs for asymptomatic hyperuricaemia; Japan's guideline considers them from 8–9 mg/dL. 135,164
- EULAR 2016: consider it from the first presentation. 331
Why some people respond less Established
ABCG2 exports urate in the kidney and gut. 153,252 Its common Q141K variant (rs2231142) predicts serum urate staying ≥6 mg/dL despite more than 300 mg/day of allopurinol in adherent people (OR 2.71, 95% CI 1.70–4.48; replication meta-analysis OR 2.43). 335,424 A genome-wide study found that ABCG2 also transports allopurinol. 428
In the pipeline Early evidence
New xanthine oxidase inhibitors and URAT1 inhibitors are in trials. Tigulixostat 200 mg brought 62.2% below 5 mg/dL at week 12 against 2.9% on placebo. 408 In China, dotinurad 4 mg brought 73.6% to ≤6 mg/dL at week 24 against 38.1% on febuxostat 40 mg. 387 Two placebo-controlled phase 3 trials of AR882 have completed. 279,281 More in Toward a cure.