Lesinurad (brand name Zurampic) is a urate transporter inhibitor for treating high blood uric acid levels associated with

gout Gout ( ) is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot and swollen joint, caused by deposition of monosodium urate monohydrate crystals. Pain typically comes on rapidly, reaching maximal intens ...

. It is only recommended together with either

allopurinol Allopurinol is a medication used to decrease high blood uric acid levels. It is specifically used to prevent gout, prevent specific types of kidney stones and for the high uric acid levels that can occur with chemotherapy. It is taken by mouth ...

or febuxostat when these medications are not sufficient. It received FDA approval on 22 December 2015. The

European Commission The European Commission (EC) is the executive of the European Union (EU). It operates as a cabinet government, with 27 members of the Commission (informally known as "Commissioners") headed by a President. It includes an administrative body ...

granted a marketing authorisation valid throughout the

European Union The European Union (EU) is a supranational political and economic union of member states that are located primarily in Europe. The union has a total area of and an estimated total population of about 447million. The EU has often been de ...

on 18 February 2016. In February 2019, it was discontinued in the United States by its manufacturer for business reasons, and was subsequently withdrawn in Europe in July 2020.

Medical uses

Lesinurad is used in combination with a

xanthine oxidase inhibitor A xanthine oxidase inhibitor is any substance that inhibits the activity of xanthine oxidase, an enzyme involved in purine metabolism. In humans, inhibition of xanthine oxidase reduces the production of uric acid, and several medications that inhi ...

, such as

or febuxostat, for treating hyperuricemia (high levels of

uric acid Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the metabolic breakdown ...

in the blood serum) associated with gout. It is approved only for patients who have not achieved target uric acid levels with a xanthine oxidase inhibitor alone.

Contraindications

The drug is contraindicated in people with

tumour lysis syndrome Tumor lysis syndrome (TLS) is a group of metabolic abnormalities that can occur as a complication from the treatment of cancer, where large amounts of tumor cells are killed off ( lysed) from the treatment, releasing their contents into the blood ...

Lesch–Nyhan syndrome Lesch–Nyhan syndrome (LNS) is a rare inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). This deficiency occurs due to mutations in the ''HPRT1'' gene located on the X chromosome. LNS ...

(juvenile gout), as well as severe impairment of kidney function, including

kidney transplant Kidney transplant or renal transplant is the organ transplant of a kidney into a patient with end-stage kidney disease (ESRD). Kidney transplant is typically classified as deceased-donor (formerly known as cadaveric) or living-donor transplantati ...

and

hemodialysis Hemodialysis, also spelled haemodialysis, or simply dialysis, is a process of purifying the blood of a person whose kidneys are not working normally. This type of dialysis achieves the extracorporeal removal of waste products such as creatinin ...

patients.: Zurampic. Accessed 19 July 2017.

Adverse drug reactions

In clinical trials,

serum creatinine Creatinine (; ) is a breakdown product of creatine phosphate from muscle and protein metabolism. It is released at a constant rate by the body (depending on muscle mass). Biological relevance Serum creatinine (a blood measurement) is an importa ...

(an important marker for kidney function) was elevated in 4.3 to 7.8% of patients depending on the dose, as compared to 2.3% under

placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. In general, placebos can af ...

. Manifest kidney problems were less frequent under the standard dose than under placebo:

Kidney failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

occurred in 2.1% of placebo patients, in 1.2% of patients with the therapeutic standard dose, and in 3.5% of patients with the double dose. For

kidney stone Kidney stone disease, also known as nephrolithiasis or urolithiasis, is a crystallopathy where a solid piece of material (kidney stone) develops in the urinary tract. Kidney stones typically form in the kidney and leave the body in the urine s ...

s, the frequencies were 1.7%, 0.6% and 2.5%, respectively. Other common side effects were influenza (5.1% vs. 2.7% under placebo), headache (5.3% vs. 4.1%), and

gastroesophageal reflux disease Gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD) is one of the upper gastrointestinal chronic diseases where stomach content persistently and regularly flows up into the esophagus, resulting in symptoms and/ ...

(2.7% vs. 0.8%).

Hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune ...

reactions were rare (<0.1%).

Interactions

The substance is a mild inducer of the liver enzyme CYP3A4. Some drugs that are metabolized by this enzyme have been shown to be slightly less effective when combined with lesinurad, examples including

simvastatin Simvastatin, sold under the brand name Zocor among others, is a statin, a type of lipid-lowering medication. It is used along with exercise, diet, and weight loss to decrease elevated lipid levels. It is also used to decrease the risk of hear ...

and

warfarin Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent st ...

. It might also be a mild inducer of

CYP2B6 Cytochrome P450 2B6 is an enzyme that in humans is encoded by the ''CYP2B6'' gene. CYP2B6 is a member of the cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances. Funct ...

. On the other hand, lesinurad concentrations in the blood are decreased by drugs that induce

CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the prote ...

and increased by substances that inhibit this enzyme (such as

fluconazole Fluconazole is an antifungal medication used for a number of fungal infections. This includes candidiasis, blastomycosis, coccidiodomycosis, cryptococcosis, histoplasmosis, dermatophytosis, and pityriasis versicolor. It is also used to pr ...

), as well as in people who have genetically determined low CYP2C9 activity. The same may be true of

microsomal epoxide hydrolase In enzymology, a microsomal epoxide hydrolase (mEH) () is an enzyme that catalyzes the hydrolysis reaction between an epoxide and water to form a diol. This enzyme plays a role in the uptake of bile salts within the large intestine. It functio ...

inhibitors (such as

valproic acid Valproate (VPA) and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those ...

). High dose

aspirin Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...

and related drugs reduce the effectiveness of other anti-gout medications. It is not known conclusively whether this also applies to lesinurad, but low dose aspirin does not negatively affect its activity.

Pharmacology

Mechanism of action

Lesinurad inhibits

URAT1 Solute carrier family 22 (organic anion/cation transporter), member 12, also known as SLC22A12 and URAT1, is a protein which in humans is encoded by the ''SLC22A12'' gene. Function The protein encoded by this gene is a urate transporter and ura ...

, a protein that is responsible for

reabsorption In renal physiology, reabsorption or tubular reabsorption is the process by which the nephron removes water and solutes from the tubular fluid (pre-urine) and returns them to the circulating blood. It is called ''reabsorption'' (and not ''absorp ...

of uric acid in the kidneys. This leads to increased uric acid excretion with the urine, and consequently lower blood levels. It also inhibits the protein OAT4, which is associated with hyperuricemia caused by

diuretic A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics i ...

drugs.

Pharmacokinetics

Lesinurad is quickly and practically completely absorbed from the gut. Highest

blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intr ...

concentrations are reached after one to four hours. When in the bloodstream, the substance is almost completely (>98%) bound to

plasma protein Blood-proteins, also termed plasma proteins, are proteins present in blood plasma. They serve many different functions, including transport of lipids, hormones, vitamins and minerals in activity and functioning of the immune system. Other blood pr ...

s, mainly

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...

. It is metabolized mainly by the liver enzyme CYP2C9 to various

oxidation Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a ...

products, predominantly to a hydroxylated substance called M3 and an

epoxide In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale ...

, M3c. The latter is quickly hydrolyzed to the diol M4 by microsomal epoxide hydrolase (mEH). The enzymes

CYP1A1 Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein that in humans is encoded by the ''CYP1A1'' gene. The protein is a member of the cytochrome P450 superfamily of enzymes. Function Metabolism of xenobiotics and drugs CYP1A1 ...

CYP2C19 Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some p ...

and CYP3A only play minor roles in its metabolization.

Glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gl ...

by the enzymes

UGT1A1 UDP-glucuronosyltransferase 1-1 also known as UGT-1A is an enzyme that in humans is encoded by the ''UGT1A1'' gene. UGT-1A is a uridine diphosphate glucuronosyltransferase (UDP-glucuronosyltransferase, UDPGT), an enzyme of the glucuronidation pat ...

and

UGT2B7 UGT2B7 (UDP-Glucuronosyltransferase-2B7) is a phase II metabolism isoenzyme found to be active in the liver, kidneys, epithelial cells of the lower gastrointestinal tract and also has been reported in the brain. In humans, UDP-Glucuronosyltrans ...

has also been detected. Lesinurad is excreted via the urine (63%) and feces (32%), with a

biological half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

of about five hours. Of the excreted dose, 30% are unchanged lesinurad, and the rest are metabolites.

Pharmacogenomics

People who are CYP2C9

poor metabolizer Pharmacogenomics is the study of the role of the genome in drug response. Its name ('' pharmaco-'' + ''genomics'') reflects its combining of pharmacology and genomics. Pharmacogenomics analyzes how the genetic makeup of an individual affects the ...

s are exposed to lesinurad concentrations that are about 1.8-fold higher than those with a normal function of this enzyme.

Chemistry

Lesinurad is a white to off-white powder and is not

hygroscopic Hygroscopy is the phenomenon of attracting and holding water molecules via either absorption or adsorption from the surrounding environment, which is usually at normal or room temperature. If water molecules become suspended among the substan ...

. It is a 1:1

racemic In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...

mixture of atropisomers.

References

External links

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