About this pathway
Background
Hyperuricemia is a build up of uric acid that can lead to pathologies such as gout and renal failure and is a symptom associated with tumor lysis syndrome (TLS) [Articles:20562597, 12646938]. The majority of uric acid found at physiological pH is in the form of urate anion [Article:20613716]. We use the term 'uric acid' here to also encompass urate. Therapeutics that treat or prevent hyperuricemia include those that inhibit the formation of uric acid, those that enhance excretion and those that prevent reabsorption. Here we discuss the role of uricosuric drugs in preventing reabsorption of uric acid in human kidney, and the genes involved in this process (see figure above). The Uric Acid-Lowering Drugs Pathway, PD covers drugs that either inhibit formation of uric acid or act directly upon uric acid to increase secretion.
Pharmacodynamics
The majority of uric acid is excreted via the kidneys, however a high proportion (around 90%) is reabsorbed by transporter proteins expressed in the renal proximal tubule [Article:20613716]. Uricosuric drugs inhibit reabsorption of uric acid in the renal proximal tubule by targeting transporters (see figure above) [Articles:20562597, 22665944]. Numerous transporters have a putative role in the secretion and reabsorption of uric acid across the luminal apical membrane of the renal proximal tubule and across the interstitial basolateral membrane; however, a clear picture of the mechanisms of uric transport has yet to be defined [Articles:22359229, 22038265]. Recent genetic analyses such as genome wide association studies (GWAS) have identified variants in novel genes associated with uric acid levels or gout and have helped in the elucidation of which proteins may be important in uric acid transport and plasma levels in humans [Articles:20613716, 22359229, 22038265, 22945592, 18606621, 18327257, 23263486, 22797727]. The current model involves a complex of proteins: the urate or uric acid 'transportasome' [Articles:22038265, 22359229, 22945592]. The transporters of the transportasome are involved in the transport of other compounds, however, here we focus on uric acid.
Known uric acid transporters
URAT1 (SLC22A12) is a transporter protein found on the apical surface of renal proximal tubule (epithelial) cells with a major role in the uptake of uric acid from the lumen [Articles:12024214, 20613716, 22359229, 22945592, 21272127]. Variants in the SLC22A12 gene identified in renal hypouricemia patients lack uric acid transport activity or display significantly decreased activity compared to wild-type URAT1 in vitro [Articles:12024214, 14694169]. Also expressed on the apical membrane of renal proximal tubule cells with a role in uric acid secretion into the glomerular filtrate/lumen are transporters encoded by ABCG2 (BCRP), SLC17A1 (NPT1) and SLC17A3 (NPT4) [Articles:20613716, 22359229, 22945592]. GLUT9 (SLC2A9) is expressed on the basolateral membrane, with a chief role in the transport of uric acid into the interstitium and blood [Articles:20613716, 22359229, 22945592]. Evidence suggests that two isoforms of GLUT9 exist - GLUT-9a (isoform 1) on the basolateral side, and GLUT-9b (isoform 2 or GLUT9N) on the apical side, though the role of the latter remains unclear [Articles:20613716, 22945592, 22359229]. In vitro, both isoforms are capable of transporting uric acid in stably expressing cells [Article:18842065].
Validating their role in uric acid transport, two recent meta-analyses of different GWAS studies (both in more than 28,000 individuals of European descent/White ethnicity), found SNPs associated with serum uric acid levels in loci containing the SLC22A12, SLC2A9, SLC17A1, SLC17A3 and ABCG2 genes, amongst other novel loci [Articles:19503597, 20884846]. A GWAS meta-analysis examining four phenotypes related to kidney function verified SLC2A9, ABCG2 and SLC22A12 loci were associated with uric acid concentration in 33,074 East Asian individuals [Article:22797727]. GWAS meta-analysis of >140,000 individuals of European descent from the Global Urate Genetics Consortium (GUGC) identified 10 previously known and 16 novel loci associated with serum urate concentrations at genome-wide significance [Article:23263486]. These loci explain 7% of the variance in urate concentrations, with SLC2A9 and ABCG2 loci contributing to 3.4% of this [Article:23263486]. 17 of the loci associated with urate concentrations were also associated with gout [Article:23263486], as has been shown previously for SLC2A9 and ABCG2 loci [Article:20884846]. Many of the SNPs associated with uric acid concentrations in the European analysis were also associated in cohorts of African-Americans (n=5,820), Japanese (n=15,286) and individuals of Indian ancestry (n=8,340), though differences are observed and may be due to variation in allele frequencies between the four different populations [Article:23263486]. Interestingly, novel loci associated with uric acid concentrations reported in recent GWAS meta-analyses include genes encoding transcription factors and genes implicated in glucose homeostasis and kidney function, revealing possible new avenues for drug discovery for reducing urate levels and preventing kidney disease [Articles:22797727, 23263486, 19503597, 20884846].
Potential uric acid transporters
Several other genes shown in the shaded section of the figure above have a potential role in uric acid transport in the human renal proximal tubule (indicated by dashed arrows). These all have in vitro evidence, and some have also been identified in GWAS related to serum uric acid concentrations and/ or gout:
- SLC22A6 (OAT1) and SLC22A8 (OAT3) are expressed on the basolateral membrane, in vitro studies show they can uptake uric acid, and knockout mice have reduced uric acid secretion [Articles:22359229, 22945592, 17674156]. In vitro, human OAT1 uptake of uric acid is inhibited by probenecid and benzbromarone [Article:12472777].
- SLC22A11 (OAT4) is localized on the apical membrane and can uptake uric acid in vitro [Articles:22359229, 20613716, 22945592, 15037815, 17674156]. SLC22A11 is upstream of the SLC22A12 gene, and several SNPs within this loci were identified with association with serum uric acid levels in meta-analyses of GWAS [Articles:19503597, 20884846]. Because SLC22A12 and SLC22A11 are in close proximately to each other on chromosome 11 it may be difficult to distinguish individual signals for association with SNPs in this loci [Article:20884846].
- SLC22A13 (OAT10) is expressed on the apical side of renal proximal tubule cells and can uptake uric acid in vitro, which is inhibited significantly by probenecid [Articles:21103968, 22038265, 18411268].
- LGALS9 (galectin 9, UAT) is proposed to have a role in the transport of uric acid from the renal proximal tubule cell at both the basolateral and apical side [Article:22359229].
- ABCC4 (MRP4) is expressed on the apical side of the renal proximal tubule cells, and as an ATP-dependent uric acid ion pump may be involved in secretion of uric acid, however there is no human or animal data to confirm this role as of yet [Articles:22359229, 20613716].
- PDZK1 encodes for a scaffold protein found close to the apical side which interacts with transporters including URAT1, OAT4 and NPT1 and may facilitate efficient uric acid transport [Articles:22359229, 22945592]. In a GWAS meta-analysis, a SNP upstream of the PDZK1 gene was associated with serum uric acid levels [Article:19503597].
Uricosuric drugs
Probenecid was originally developed to inhibit renal secretion of penicillin, before the discovery of its benefits in gout patients [Article:23318701]. It prevents the reabsorption of organic anions such as uric acid from the renal proximal tubule predominantly by inhibiting URAT1 (SLC22A12) transporter protein activity [Articles:12024214, 22359229, 22665944, 23318701, 21272127]. In vitro, probenecid does not seem to have an effect on GLUT9 (SLC2A9) at an effective pharmacological concentration of 1mM [Article:18842065]. Probenecid may also prevent uric acid reabsorption by acting upon OAT1 (SLC22A6), OAT4 (SLC22A11) and OAT10 [Articles:23318701, 12472777, 18411268]. As a consequence, probenecid can alter the clearance of drugs taken concomitantly, and can affect caffeine metabolism [Articles:11823755, 4020675, 23436258, 17725176]. Probenecid's inhibition of SLC22A8 (OAT3) could mean it is a potential treatment strategy for influenza A infection [Article:23129053]. Benzbromarone inhibits uric acid transport by URAT1 (SLC22A12) and GLUT-9 (SLC2A9) in vitro, though at therapeutic doses its action upon GLUT-9 may be minimal [Articles:23318701, 22945592, 18670416, 18636784, 12024214, 21272127, 18842065]. It also displays action against uric acid uptake by OAT1 (SLC22A6) in vitro [Article:12472777]. Sulfinpyrazone inhibits uric acid uptake by URAT1 (SLC22A12) in vitro, and reduces serum uric acid in vivo [Articles:12024214, 1948784, 668783]. It also inhibits the activity of other transporters including ABCC1, ABCC2 and ABCC10 [Articles:18445659, 14569069, 9685354].
Other drugs with uricosuric properties
Used for hypertension treatment, losartan is a unique angiotensin II receptor antagonist in that it also increases uric acid secretion and significantly decreases plasma levels by inhibiting reabsorption in the renal proximal tubule, targeting transporter proteins URAT1 (SLC22A12) [Articles:8743498, 18670416, 12024214]. Tranilast is an anti-inflammatory, however also exhibits uricosuric properties by inhibiting URAT1 and GLUT9, thus these combined effects make it a potential gout therapeutic [Article:23318701]. Vitamin c is thought to act as a uricosuric by inhibiting reabsorption of uric acid by URAT1 (SLC22A12) [Article:23253231]. Studies have revealed that doses of 500mg/daily may reduce serum uric acid and doses of >1000mg/daily may reduce risk of gout [Article:22198943]. Salicylate/salicylic acid and indomethacin also inhibit uric acid uptake by URAT1 (SLC22A12) in vitro [Articles:12024214, 21272127].
Pharmacogenomics (PGx)
As well as influencing plasma uric acid levels and risk of gout, polymorphisms in transporter genes may also affect the efficacy of uricosurics to inhibit reabsorption. There is however currently few published PGx studies investigating uricosurics. Below are the genetic associations with uricosurics found in an extensive literature search. The figure above illustrates genes involved in the regulation of uric acid transport, highlighting potential novel drug targets and potential genes of interest for future pharmacogenetic studies. Polymorphisms in genes involved in the metabolism of these drugs may also influence their toxicity and efficacy.
SLC22A12 (URAT1)
Numerous variants within SLC22A12 have been identified in patients with hypouricemia, some of which display reduced uric acid uptake in vitro [Articles:14694169, 12024214, 18492088, 15327384]. There is some evidence to suggest that these variants may affect response to uricosuric and anti-uricosuric drugs that act upon URAT1. Amongst hypertensive patients (without hypouricemia) with wildtype SLC22A12, benzbromarone or losartan treatments significantly increase in uric acid clearance (Cur)/creatinine clearance (Ccr) ratio (indicating a decrease in serum uric acid). In patients with hypertension and hypouricemia who were homozygous or compound heterozygous for variants in the SLC22A12 gene, benzbromarone or losartan treatment had no effect on the Cur/Ccr ratio (indicating a lack of effect on serum uric acid levels). Losartan was still able to maintain its hypotensive effect on blood pressure in these patients [Article:18670416]. These variants included rs121907896 G269A (Arg90His) and rs121907892 G774A Trp258Ter (c.NM_144585.2); both identified in patients with idiopathic renal hypouricemia, associated with reduced uric acid uptake in vitro and lower residuals of serum uric acid levels compared to wild-type in subjects [Articles:12024214, 15327384, 14694169]. This lack of response to benzbromarone in hypouricemia patients with SLC22A12 variants that reduce uric acid transport is supported by another study, which also observed an effect on the anti-uricosuric activity of pyrazinamide [Article:14694169]. This may have implications for the treatment of hypouricemic patients.
CYP2C9
Due to reports of fatal hepatotoxicity, benzbromarone was withdrawn from the market by one of its main manufacturers, though this is regarded by some as premature and it is still available from other drug companies in several countries across the globe [Articles:18636784, 22933344]. Genetics could be a factor that influences toxicity risk. Benzbromarone is metabolized by CYP2C9 to form the active metabolite 6-hydroxybenzbromarone (which has inhibitory activity upon URAT1 uric acid uptake) and by CYP3A4 to form 1'- hydroxybenzbromarone [Articles:22933344, 18636784, 18020424, 21272127]. 6-hydroxybenzbromarone is further metabolized to 5,6-dihydroxybenzbromarone by CYP2C9 and CYP1A2 [Article:22933344]. A small study in 20 healthy individuals saw reduced metabolism and clearance of benzbromarone in an individual with the CYP2C9*3/*3 genotype compared to those with *1/*1 or *1/*3 genotypes, and a significantly higher elimination half life of 6-hydroxybenzbromarone in patients with the *1/*3 genotype compared to *1/*1 [Article:20962433]. Whether CYP2C9 genotype may have a clinically relevant effect on benzbromarone pharmacodynamics is unknown; the study saw no differences in uric acid excretion or plasma concentrations were observed [Article:20962433]. Polymorphisms in CYP2C9 that result in higher plasma levels of benzbromarone and reduced metabolism to 6-hydroxybenzbromarone could contribute to toxicity: both benzbromarone and 1'- hydroxybenzbromarone display cytotoxic effects in vitro [Article:23229783] and 5,6-dihydroxybenzbromarone may also result in toxicity [Article:18020424]. The CYP2C9 dependent sequential oxidations forming the 5,6-catechol has the potential for forming a reactive quinone, which is supported by forming glutathione adducts in vitro [Article:18020424]. This reaction profile is typical of several other hepatotoxic drugs. It has been recommended that CYP2C9 genotyping be carried out in cases of benzbromarine-induced hepatotoxicity [Article:18636784], in order to begin to capture more evidence for whether an association between CYP2C9 genotype and benzbromarone toxicity exists. Polymorphisms in CYP2C9 may also alter drug-drug interactions. Benzbromarone inhibits metabolism of flurbiprofen (an anti-inflammatory agent) by CYP2C9.1, however metabolism of flurbiprofen by CYP2C9.3 is activated in the presence of benzbromarone [Article:15955872].
ABCB1 and ABCC2
To date, no pharmacogenetic studies were found that have examined the direct effect on uric acid secretion of genetic variants directed at probenecid targets. Several studies have however examined other drugs, using probenecid as an inhibitor. In a small study, probenecid reduced clearance and distribution of the drug dicloxacillin, and a SNP within exon 26 of ABCB1 were shown to affect dicloxacillin urinary excretion when probenecid was co-administered [Article:18576903], indicating possible genetic effects on probenecid efficacy as an inhibitor, though further study is required. Probenecid inhibits efflux of carboxyfluorescein transport through wildtype MRP2 protein in vitro [Article:11477083]. Two variants of the ABCC2 gene (encodes MRP2), associated with Dubin-Johnson Syndrome, confer impaired transport activity (R11150H 3449G>A, 3517A>T I1173F) [Article:11477083], these variants may therefore affect probenecid's action on this transporter.
UGT1A1
Intrinsic clearance of sulfinpyrazone by UGT1A9 glucuronidation was shown to be significantly lower in cells expressing the UGT1A9 variant Met33Thr (rs72551330 allele C) compared to Met33 (allele T) [Article:22981363].
Summary
As around 90% of uric acid cleared by the body is reabsorbed in the renal proximal tubule. Drugs targeting transporters involved in reabsorption have been developed for the treatment of hyperuricemia/gout. A clear picture of the mechanisms involved is still to be elucidated, but here we provide known and potential genes involved in uric acid transport within renal proximal tubule cells and which are targeted by uricosuric drugs. Further research into the effects of polymorphisms in these genes on the uricosuric action of these drugs may provide insights into treatment efficacy or novel targets for drug development.
Reactions & interactions (34)
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Activation
PDZK1 → SLC22A12
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Catalysis
SLC2A9 → Transport
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Catalysis
SLC22A13 → Transport
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Catalysis
SLC22A12 → Transport
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Catalysis
SLC22A11 → Transport
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Catalysis
LGALS9 → Transport
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Catalysis
SLC2A9 → Transport
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Catalysis
SLC17A1 → Transport
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Catalysis
SLC2A9 → Transport
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Catalysis
LGALS9 → Transport
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Catalysis
SLC17A3 → Transport
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Catalysis
ABCG2 → Transport
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Catalysis
ABCC4 → Transport
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Catalysis
SLC22A8 → Transport
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Catalysis
SLC22A6 → Transport
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Inhibition
sulfinpyrazone → SLC22A12
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Inhibition
benzbromarone → SLC2A9
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Inhibition
tranilast → SLC2A9
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Inhibition
benzbromarone → SLC22A12
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Inhibition
probenecid → SLC22A12
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Inhibition
losartan → SLC22A12
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Inhibition
tranilast → SLC22A12
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Inhibition
vitamin c → SLC22A12
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Inhibition
indomethacin → SLC22A12
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Inhibition
salicyclic acid → SLC22A12
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Inhibition
probenecid → SLC22A11
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Inhibition
probenecid → SLC22A13
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Inhibition
probenecid → SLC22A6
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Inhibition
benzbromarone → SLC22A6
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Leads To
uric acid → Uric Acid-Lowering Drugs Pathway, Pharmacodynamics
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Transport
uric acid → uric acid
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Transport
uric acid → uric acid
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Transport
uric acid → uric acid
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Transport
uric acid → uric acid
Edit history (6)
- 2013-12-17 Create
- 2014-06-12 Update Added publication to citation
- 2019-06-27 Update Updated gpml to new format. Moved PDZ1 to interact directly with SLC22A12 and added extra reference [18600508].
- 2019-06-27 Update Updated to new illustrator format.
- 2024-08-27 Update fixed typos
- 2025-07-17 Update Removed name PharmGKB pathway