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].

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].

Absorption, Distribution and Excretion
Oral lesinurad is rapidly absorbed, reaching maximum plasma concentrations (Cmax) within 1–4 h following the administration a single 200 mg dose (in either the fed or fasted state).
Within 7 days following single dosing of radiolabeled lesinurad, 63% of administered radioactive dose was recovered in urine and 32% of administered radioactive dose was recovered in feces. Most of the radioactivity recovered in urine (> 60% of dose) occurred in the first 24 hours. Unchanged lesinurad in urine accounted for approximately 30% of the dose.
The mean steady state volume of distribution of lesinurad was approximately 20 L following intravenous dosing.

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Metabolism / Metabolites
Lesinurad undergoes oxidative metabolism mainly via the polymorphic cytochrome P450 CYP2C9 enzyme.

Hepatotoxicity
In large clinical trials, serum enzyme elevations were rare during lesinurad therapy and no more common than with placebo, and no instances of clinically apparent liver injury attributable to lesinurad were reported. Clinical experience with lesinurad therapy has been limited, but there have yet to be reports of clinically apparent liver injury attributable to its use.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Protein Binding
Lesinurad is extensively bound to proteins in plasma (greater than 98%), mainly to albumin.

[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 member of the class of triazoles that is [(3-bromo-1,2,4-triazol-5-yl)sulfanyl]acetic acid substituted at position 1 of the triazole ring by a 4-cyclopropylnaphthalen-1-yl group. Used for treatment of gout. It has a role as a uricosuric drug. It is a member of triazoles, a member of naphthalenes, a member of cyclopropanes, an organobromine compound, an aryl sulfide and a monocarboxylic acid.
Lesinurad is an oral uric acid transporter 1 (URAT1) inhibitor indicated for the treatment of hyperuricemia associated with gout. It reduces serum uric acid concentration through the inhibition of URAT1, an enzyme responsible for reuptake of uric acid from the renal tubule, and OAT4, another uric acid transporter associated with diuretic-induced hyperuricemia. Marketed as the product Zurampic, it is indicated for use in combination with a xanthine oxidase inhibitor for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone. In August 2017, a combination oral therapy consisting of lesinurad and [DB00437] was FDA-approved under the brand name Duzallo indicated for the treatment of gout-related hyperuricemia in patients with uncontrolled gout.
Lesinurad is an Urate Transporter 1 Inhibitor. The mechanism of action of lesinurad is as an Urate Transporter 1 Inhibitor, and Cytochrome P450 3A Inducer.
Lesinurad is a selective inhibitor of uric acid reabsorption which is used in combination with other agents in the therapy of gout. Lesinurad has had limited clinical use, but has not been associated with serum enzyme elevations during therapy or with instances of clinically apparent liver injury.
See also: Allopurinol; Lesinurad (component of).

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Drug Indication
For use, in combination with a xanthine oxidase inhibitor, for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone.
FDA Label
Zurampic, in combination with a xanthine oxidase inhibitor, is indicated in adults for the adjunctive treatment of hyperuricaemia in gout patients (with or without tophi) who have not achieved target serum uric acid levels with an adequate dose of a xanthine oxidase inhibitor alone. ,
Prevention of hyperuricaemia, Treatment of hyperuricaemia

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Mechanism of Action
Lesinurad inhibits the activity of uric acid transporter 1 (URAT1) and organic anion transporter 4 (OAT4). URAT1 is a major transporter enzyme responsible for reuptake of uric acid from the renal tubules; inhibition of URAT1 function thereby increases excretion of uric acid.

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Pharmacodynamics
Dose-dependent reductions in serum uric acid levels and increases in urinary uric acid excretion have been observed following single and multiple oral doses of lesinurad.

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.)