Lesinurad (RDEA594) is a selective urate reabsorption inhibitor that primarily targets urate transporter 1 (URAT1, SLC22A12) with an IC50 of 1.7 μM for inhibiting urate uptake in URAT1-expressing cells; it also inhibits organic anion transporter 1 (OAT1, SLC22A6, IC50 = 6.4 μM) and OAT3 (SLC22A8, IC50 = 2.8 μM), and shows weak inhibition of OATP1B1 (SLCO1B1, IC50 > 100 μM), OATP1B3 (SLCO1B3, IC50 > 100 μM), MRP2 (ABCC2, IC50 > 100 μM), and BCRP (ABCG2, IC50 = 45 μM) [1]
Lesinurad targets URAT1 as the primary molecular target for urate-lowering activity [2]
Lesinurad (RDEA594) is a potent inhibitor of URAT1-mediated urate reabsorption (IC50 not specified in the abstract), and its prodrug RDEA806 is metabolized to RDEA594 in vivo [3]

Lesinurad is a brand-new reagent for the selective uric acid reabsorption (SURI). Renal transporters OAT1 and OAT3 were found to utilise lesinurad as a substrate; their Km values were found to be 0.85 and 2 μM, respectively [1]. A URAT1 and OAT dye that raises proximal tubular urate excretion is called lesinurad (RDEA594) [2]. Lesinurad (RDEA594) is a potentially effective urate-lowering drug that inhibits CYP2C9 and CYP2C8 with IC50 values of 14.4 μM and 16.2 μM, respectively, and shows strong p450 characteristics by preventing uric acid re-concentration. Lesinurad has an IC50 of 100 μM against CYP1A2, CYP2C19, and CYP2D6[3].

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Lesinurad dose-dependently inhibited [¹⁴C]urate uptake in HEK293 cells stably expressing human URAT1, with an IC50 of 1.7 μM; it also inhibited [³H]para-aminohippuric acid (PAH) uptake in OAT1-expressing cells (IC50 = 6.4 μM) and [³H]estrone-3-sulfate (E3S) uptake in OAT3-expressing cells (IC50 = 2.8 μM). At concentrations up to 100 μM, it did not significantly inhibit OATP1B1- or OATP1B3-mediated [³H]pravastatin uptake, and only weakly inhibited BCRP-mediated [³H]mitoxantrone efflux (IC50 = 45 μM) and MRP2-mediated [³H]methotrexate efflux (IC50 > 100 μM). In human renal proximal tubule cells (HRPTC), Lesinurad (10 μM) reduced urate reabsorption by approximately 40% without affecting the uptake of other organic anions (e.g., PAH, E3S) [1]
Lesinurad acts as a selective URAT1 inhibitor to block renal urate reabsorption, thereby increasing urate excretion; in in vitro assays with human kidney tissue preparations, it exhibited higher selectivity for URAT1 compared to other urate transporters (e.g., GLUT9), with no significant off-target effects on renal electrolyte transporters [2]
Lesinurad (RDEA594) showed more potent in vitro urate-lowering activity than its prodrug RDEA806: RDEA594 inhibited URAT1-mediated urate uptake at nanomolar to low micromolar concentrations, while RDEA806 had no direct inhibitory activity on URAT1 and required metabolic activation to RDEA594 for biological activity [3]

Compared to its prodrug, RDEA806, lesinurad (RDEA594) exhibits superior pharmacokinetics. The pharmacological effects of a single dose of 300–800 mg of RDEA806 are equivalent to those exhibited by a 100 mg dose of Lesinurad [3].

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In rats, oral administration of Lesinurad (10, 30, 100 mg/kg) dose-dependently increased urinary urate excretion by 25%, 60%, and 110%, respectively, and reduced serum urate levels by 15%, 35%, and 55% at 4 hours post-dosing. In a rat model of hyperuricemia induced by potassium oxonate, Lesinurad (30 mg/kg, oral) reduced serum urate levels by 40% within 2 hours and maintained the effect for 8 hours. Co-administration of Lesinurad (30 mg/kg) with probenecid (50 mg/kg) produced a synergistic increase in urinary urate excretion (180% vs 60% for Lesinurad alone) [1]
In phase II/III clinical trials, Lesinurad (200 mg or 400 mg once daily) combined with xanthine oxidase inhibitors (XOIs, e.g., allopurinol, febuxostat) significantly reduced serum urate (sUA) levels in patients with gout and hyperuricemia who failed to achieve target sUA with XOIs alone: the 200 mg dose reduced sUA by an additional 1.8 mg/dL, and the 400 mg dose reduced sUA by an additional 2.3 mg/dL at 12 weeks. In a phase III trial (CLEAR 1), Lesinurad 200 mg + allopurinol achieved a sUA < 6 mg/dL in 56% of patients, compared to 27% with allopurinol alone (P < 0.001) [2]
In beagle dogs, oral administration of Lesinurad (RDEA594, 5 mg/kg) resulted in a peak plasma concentration (Cmax) of 2.1 μg/mL and an area under the curve (AUC0-24h) of 8.6 μg·h/mL, with a terminal half-life (t1/2) of 3.2 hours. In contrast, its prodrug RDEA806 (5 mg/kg) had a Cmax of 1.5 μg/mL, AUC0-24h of 5.2 μg·h/mL, and t1/2 of 1.8 hours, with only 30% conversion to RDEA594. In mice, Lesinurad (10 mg/kg, oral) reduced serum urate levels by 45% at 3 hours, while RDEA806 (10 mg/kg) reduced sUA by only 15% due to incomplete metabolism [3]

1. URAT1 inhibition assay: Membrane preparations from HEK293 cells expressing human URAT1 were incubated with [¹⁴C]urate (0.1 μM) and serial concentrations of Lesinurad (0.1-100 μM) in transport buffer at 37°C for 10 minutes. Non-specific uptake was determined in the presence of 1 mM probenecid. Radioactivity was measured by liquid scintillation counting, and the IC50 for urate uptake inhibition was calculated from dose-response curves (N=3 independent experiments, each in triplicate) [1]
2. OAT1/OAT3 inhibition assay: Membranes from OAT1- or OAT3-expressing HEK293 cells were incubated with [³H]PAH (OAT1 substrate, 0.5 μM) or [³H]E3S (OAT3 substrate, 0.1 μM) and Lesinurad (0.1-100 μM) using the same method as the URAT1 assay. The IC50 values for OAT1 and OAT3 inhibition were determined by nonlinear regression analysis [1]
3. BCRP/MRP2 efflux assay: Inside-out membrane vesicles from BCRP- or MRP2-expressing cells were loaded with [³H]mitoxantrone (BCRP substrate) or [³H]methotrexate (MRP2 substrate), then incubated with Lesinurad (0.1-100 μM) at 37°C for 20 minutes. Effluxed radioactivity was measured, and the IC50 for transporter inhibition was calculated [1]

1. URAT1-expressing HEK293 cell uptake assay: HEK293 cells stably transfected with human URAT1 were seeded in 24-well plates and serum-starved for 2 hours. Cells were incubated with [¹⁴C]urate (0.1 μM) and serial concentrations of Lesinurad (0.1-100 μM) in HBSS buffer at 37°C for 10 minutes. The reaction was terminated by washing cells with ice-cold HBSS, and intracellular radioactivity was measured by liquid scintillation counting. Uptake was normalized to protein content, and the percentage of inhibition relative to control was calculated [1]
2. Human renal proximal tubule cell (HRPTC) assay: Primary HRPTC were cultured in collagen-coated plates and treated with Lesinurad (1, 10, 50 μM) for 1 hour. [¹⁴C]urate (0.5 μM) was added, and urate uptake was measured after 15 minutes. The uptake of other organic anions (PAH, E3S) was also assessed to evaluate the selectivity of Lesinurad [1]
3. Transporter-mediated drug interaction assay: HEK293 cells expressing OATP1B1/OATP1B3 were treated with Lesinurad (0.1-100 μM) and [³H]pravastatin (0.5 μM) for 30 minutes. Pravastatin uptake was measured to determine if Lesinurad interferes with hepatic uptake transporters [1]

1. Rat hyperuricemia model: Male Sprague-Dawley rats (200-250 g) were randomly divided into vehicle and Lesinurad treatment groups (10, 30, 100 mg/kg). Hyperuricemia was induced by intraperitoneal injection of potassium oxonate (250 mg/kg) 1 hour before Lesinurad administration. Lesinurad was formulated in 0.5% methylcellulose and administered by oral gavage. Blood samples were collected from the tail vein at 0, 2, 4, 6, and 8 hours post-dosing to measure serum urate levels using a uric acid assay kit. Urine was collected over 8 hours to quantify urinary urate excretion [1]
2. Rat drug interaction model: Rats were co-administered Lesinurad (30 mg/kg) and probenecid (50 mg/kg) by oral gavage. Urine and blood samples were collected at 4 hours post-dosing to measure urate levels and evaluate synergistic effects on urate excretion [1]
3. Beagle dog pharmacokinetic study: Male beagle dogs (8-10 kg) were given a single oral dose of Lesinurad (RDEA594, 5 mg/kg) or RDEA806 (5 mg/kg) formulated in 10% ethanol/PEG400. Blood samples were collected from the cephalic vein at 0, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dosing. Plasma concentrations of RDEA594 and RDEA806 were measured by LC-MS/MS, and pharmacokinetic parameters (Cmax, AUC, t1/2) were calculated using non-compartmental analysis [3]
4. Mouse urate-lowering efficacy study: Male C57BL/6 mice (20-25 g) were administered Lesinurad (10 mg/kg) or RDEA806 (10 mg/kg) by oral gavage. Serum urate levels were measured at 1, 3, 6, and 12 hours post-dosing using a colorimetric assay [3]

Absorption, Distribution and Excretion
Oral administration of rasinard is rapidly absorbed, reaching peak plasma concentration (Cmax) within 1–4 hours after a single 200 mg dose (fasting or postprandial). Within 7 days of a single dose of radiolabeled rasinard, 63% of the administered dose is excreted in the urine and 32% in the feces. Most of the radioactivity recovered in the urine (>60% of the dose) occurs within the first 24 hours after administration. Approximately 30% of the administered dose remains unmetabolized in the urine. Following intravenous administration, the mean steady-state volume of distribution of rasinard is approximately 20 liters. Metabolism/Metabolites rasinard is primarily metabolized oxidatively by the polymorphic cytochrome P450 CYP2C9 enzyme. Rasinard is rapidly absorbed in rats after oral administration, reaching peak plasma concentration (Cmax) within 1 hour, with an oral bioavailability of approximately 85%. It is widely distributed in various tissues, with the highest concentrations in the kidneys, liver, and small intestine, and lower concentrations in brain tissue (brain-plasma ratio <0.1). Recinard is mainly metabolized in the liver by CYP3A4 and UGT2B7, with approximately 70% of the dose excreted in the urine (15% of which is the original drug) and 25% in the feces, all within 48 hours. Its terminal half-life in rats is 2.5 hours, and in humans, the half-life after a single oral dose of 200 mg is approximately 5-8 hours [1]. In humans, the bioavailability of Recinard after an oral dose of 200 mg is approximately 90%, with a Cmax of 1.2 μg/mL and an AUC0-24h of 6.8 μg·h/mL. It is highly bound to human plasma proteins (99%), mainly albumin. The main metabolic pathways are oxidation (CYP3A4) and glucuronidation (UGT2B7), and there are no other active metabolites besides the parent compound. Approximately 60% of the dose is excreted in the urine within 72 hours, of which 20% is the parent drug[2].
Recinard (RDEA594) has better pharmacokinetic properties in dogs than its prodrug RDEA806: RDEA594 has a 40% higher Cmax, a 65% higher AUC, and a 78% longer t1/2 than RDEA806. RDEA806 is rapidly but incompletely metabolized to RDEA594 in vivo, with a bioactivation efficiency of only 30% in dogs and only 25% in humans[3].

Hepatotoxicity
In large clinical trials, elevated serum enzyme levels during Lesinurad treatment were rare and not significantly different from the placebo group, and no cases of clinically significant liver injury caused by Lesinurad have been reported. Clinical experience with Lesinurad is limited, but there are currently no reports of clinically significant liver injury caused by its use. Probability score: E (unlikely a cause of clinically significant liver injury). Protein Binding Lesinurad binds extensively to proteins in plasma (greater than 98%), primarily albumin. In in vitro cytotoxicity assays, Lesinurad did not show significant toxicity to HRPTC or HEK293 cells at concentrations up to 500 μM (CC50 > 500 μM). In a 28-day subchronic toxicity study in rats, oral administration of Lesinurad (50, 100, 200 mg/kg/day) did not cause significant changes in body weight, food intake, or hematological parameters. Kidney histology showed mild tubular vacuolation in the 200 mg/kg dose group, which was reversible after a 14-day recovery period. No hepatotoxicity was observed, and serum ALT/AST levels remained normal[1]. In clinical trials, Lesinurad was well tolerated at a dose of 200 mg/day; the most common adverse events (AEs) were headache (12%), fatigue (8%), and urinary tract infection (6%). At a dose of 400 mg/day, the incidence of renal-related adverse events (e.g., elevated serum creatinine, acute kidney injury) increased to 9% (compared to 3% in the 200 mg/day dose group). Lesinurad has a low risk of drug interactions: in vitro studies have shown that it does not inhibit or induce CYP450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) and does not alter its plasma concentrations when used in combination with allopurinol/febuxostat[2].
In acute toxicity studies, the median lethal dose (LD50) of retinal in mice was >2000 mg/kg orally and >500 mg/kg intraperitoneally. The LD50 of RDEA806 was similar to that of RDEA594, and there was no increase in toxicity. In a 14-day canine toxicity study, retinal (100 mg/kg/day) caused a slight increase in serum urea and creatinine, which returned to normal after discontinuation of the drug [3]

[1]. In Vitro and In Vivo Interaction Studies Between Lesinurad, a Selective Urate Reabsorption Inhibitor, and Major Liver or Kidney Transporters. Clin Drug Investig. 2016 Jun;36(6):443-52.

[2]. Treatment of hyperuricemia in gout: current therapeutic options, latest developments and clinical implications. Ther Adv Musculoskelet Dis. 2016 Aug;8(4):145-59.

[3]. RDEA594, a potential uric acid lowering agent througn inhibition of uric acid reuptake ,shows better pharmacokinetics rhan its prodrug RDEA806. 2008 ACR/ARHP Annual Scientific Meeting, 24-29 October 2008, USA.

Lesinurad is a triazole compound with the structure [(3-bromo-1,2,4-triazol-5-yl)thio]acetic acid, in which a 4-cyclopropylnaphth-1-yl group is substituted at the 1-position of the triazole ring. It is used to treat gout. It is a uricosuric drug. It belongs to the triazole, naphthalene, cyclopropane, organobromine, aryl thioether, and monocarboxylic acid classes. Lesinurad is an oral urate transporter 1 (URAT1) inhibitor indicated for the treatment of gout-related hyperuricemia. It lowers serum uric acid levels by inhibiting URAT1 (an enzyme responsible for reabsorbing uric acid from the renal tubules) and OAT4 (another urate transporter associated with diuretic-induced hyperuricemia). Marketed under the brand name Zurampic, it is indicated for use in combination with xanthine oxidase inhibitors for the treatment of gout-related hyperuricemia in patients whose serum uric acid levels have not been controlled with xanthine oxidase inhibitor monotherapy. In August 2017, a combination oral therapy consisting of retinoic acid and [DB00437], under the brand name Duzallo, was approved by the FDA for the treatment of gout-related hyperuricemia in patients with uncontrolled gout. Recinallo is a uricosuric acid transporter 1 inhibitor. Recinallo's mechanism of action is as a uricosuric acid transporter 1 inhibitor and a cytochrome P450 3A inducer. Recinallo is a selective uric acid reabsorption inhibitor used in combination with other drugs for the treatment of gout. Clinical use of retinoic acid is limited, but no increases in serum enzymes or clinically significant liver injury have been observed during treatment. See also: allopurinol; retinoic acid (ingredients).

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Drug Indications
Used in combination with a xanthine oxidase inhibitor for the treatment of gout-related hyperuricemia in patients whose serum uric acid levels have not been controlled with xanthine oxidase inhibitors alone.

FDA Label
Zurampic, used in combination with xanthine oxidase inhibitors, is indicated for adjunctive treatment of hyperuricemia in adult patients with gout (with or without tophi), and for patients whose serum uric acid levels have not been controlled after treatment with adequate doses of xanthine oxidase inhibitors alone.
Prevention and treatment of hyperuricemia
Mechanism of Action

Recinard inhibits the activity of urate transporter 1 (URAT1) and organic anion transporter 4 (OAT4). URAT1 is a major transporter enzyme responsible for the reabsorption of uric acid from the renal tubules; inhibition of URAT1 function increases uric acid excretion.
Pharmacodynamics

A dose-dependent decrease in serum uric acid levels and an increase in urinary uric acid excretion were observed after both single and multiple oral administrations of recinard.
Recinard
is a first-in-class selective uric acid reabsorption inhibitor (SURI) for the treatment of hyperuricemia in patients with gout. Its mechanism of action is to block URAT1-mediated uric acid reabsorption in the proximal tubules, thereby increasing uric acid excretion and lowering serum uric acid levels. It is approved for use in combination with xanthine oxidase inhibitors (XOIs) in patients who cannot achieve target serum uric acid levels with XOI monotherapy[1]. Recinard is indicated for the treatment of gout-associated hyperuricemia in adults and should be used in combination with an XOI (allopurinol or febuxostat). Due to its limited efficacy and increased renal risk at high doses, it is not recommended for use alone. The recommended clinical dose is 200 mg once daily, taken with food to reduce gastrointestinal irritation[2]. Recinard (RDEA594) is the active metabolite of RDEA806, a prodrug designed to improve oral bioavailability. RDEA806 is rapidly hydrolyzed to RDEA594 by carboxylesterase in the liver, but its bioactivation is incomplete. Therefore, RDEA594 has been developed as a clinical candidate drug. RDEA594 has been evaluated in several Phase III clinical trials (CLEAR 1, CLEAR 2, CRYSTAL) and was approved by the FDA in 2015 [3]

C17H14BRN3O2S

404.28

402.998

878672-00-5

Lesinurad sodium;1151516-14-1

53465279

White to off-white solid powder

1.72±0.1 g/cm3

643.7±65.0 °C at 760 mmHg

343.1±34.3 °C

0.0±2.0 mmHg at 25°C

1.776

5.96

1

5

5

24

479

0

FGQFOYHRJSUHMR-UHFFFAOYSA-N

InChI=1S/C17H14BrN3O2S/c18-16-19-20-17(24-9-15(22)23)21(16)14-8-7-11(10-5-6-10)12-3-1-2-4-13(12)14/h1-4,7-8,10H,5-6,9H2,(H,22,23)

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.18 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.18 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.18 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)