Pharmacological urate-lowering approaches in chronic kidney disease

Accepted Manuscript Pharmacological urate-lowering approaches in chronic kidney disease Xinrui Li, Jing Liu, Liang Ma, Ping Fu PII:

S0223-5234(19)30063-7

DOI:

https://doi.org/10.1016/j.ejmech.2019.01.043

Reference:

EJMECH 11050

To appear in:

European Journal of Medicinal Chemistry

Received Date: 7 December 2018 Revised Date:

20 January 2019

Accepted Date: 20 January 2019

Please cite this article as: X. Li, J. Liu, L. Ma, P. Fu, Pharmacological urate-lowering approaches in chronic kidney disease, European Journal of Medicinal Chemistry (2019), doi: https://doi.org/10.1016/ j.ejmech.2019.01.043. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Pharmacological urate-lowering approaches in chronic kidney disease Xinrui Li, Jing Liu, Liang Ma*, Ping Fu

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Kidney Research Laboratory, Division of Nephrology and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041,

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China.

Correspondence: Liang Ma and Ping Fu, Kidney Research Laboratory, Division of

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Nephrology, West China Hospital of Sichuan University, Guoxue alley 37#, Chengdu 610041, China. Tel.: 86 28 85164167. Email: [email protected] (L Ma), and

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[email protected] (P Fu).

ACCEPTED MANUSCRIPT Abstract Chronic kidney disease (CKD) has become a global public health issue and uric acid (UA) remains a major risk factor of CKD. As the main organ for the elimination of

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UA, kidney owned a group of urate transporters in tubular epithelium. Kidney disease hampered the UA excretion, and the accumulation of serum UA in return harmed the renal function. Commercially, there are three kinds of agents targeting at

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urate-lowering, xanthine oxidoreductase inhibitor which prevents the production of

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UA, uricosuric which increases the concentration of UA in urine thus decreasing serum UA level, and uricase which converts UA to allantoin resulting in the dramatic decrement of serum UA. Of note, in patients with CKD, administration of above-mentioned agents, alone or combined, needs special attention. New evidence is

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emerging for the efficacy of several urate-lowering drugs for the treatment of hyperuricemia in patients with CKD. Besides, loads of novel and promising drug

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candidates and phytochemicals are in the different phases of research and development. As of today, there is insufficient evidence to recommend the widespread

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use of UA-lowering therapy to prevent or slow down the progression of CKD. The review summarized the evidence and perspectives about the treatment of hyperuricemia with CKD for medicinal chemist and nephrologist. Keywords Chronic kidney disease, uric acid, xanthine oxidase, urate-lowering treatment

ACCEPTED MANUSCRIPT 1. Introduction For human, uric acid (UA) is the terminal product of purines, which are biologically synthesized

as

nucleotides

(e.g.

monophosphate

adenine

and

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monophosphate guanine), due to the lack of urate oxidase gene. [1] Conversion from the purine-derived nucleotides to UA needs a series of enzymes, among which, xanthine oxidoreductase (XOR) plays a pivotal role. XOR contains two

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interconvertible forms, xanthine oxidase and xanthine dehydrogenase, and is

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disbursed over various organs such as liver, intestine, lung, kidney, heart, brain and plasma. [2]

Kidney is responsible for the most of elimination of UA, while the remaining is accomplished by gut (approximately 30%). [3] UA chiefly subsists as Na+-urate in

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plasma and is freely filtered by the glomerulus. Besides, in proximal tubule, urate is secreted by the facilitated mechanism. Reabsorption also happens in proximal tubule, depending on the coordination of transporters wherein Na+-dependent absorption of

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anions primes tubular cells for urate transport. [4] Located in the brush border

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membrane, ABCG2 (ATP-binding cassette super-family G member 2) is a urate efflux transporter, while MRP4 (multi-drug resistance protein 4) is considered as a unidirectional export pump for urate.[5, 6] Sodium-dependent phosphate transporters form a family of organic anion transport proteins.[7] NPT1 and NPT4 (sodium-dependent phosphate transporter type 1 and 4) are two members of the family that are associated with urate secretion.[8, 9] Organic anion transporter (OAT) family is another correspondent to the organic anion transport system in the kidney.

ACCEPTED MANUSCRIPT [10] OAT1-3 proteins are on the basolateral membrane of proximal tubule for the uptake of urate from blood and operating as exchangers for mediating urate efflux.[11, 12] On the contrary, OAT4 and OAT10 are on the luminal side, of whom elevated

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expression is associated with renal underexcretion type hyperuricemia.[13, 14] The main transporter in the luminal epithelium of proximal tubule for urate reabsorption is URAT1 (Urate transporter 1). Compared with those multi-specific OATs, URAT1

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possessed much more selective affinity to substrates. [15] GLUT9, a member of the

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facilitative glucose transporter family, was identified as both a fructose and a urate transporter, which could stimulate the urate reabsorption by transporting fructose.[16] It plays the most significant role in urate reabsorption since it is the sole pathway for UA going back to plasma. Further research disclosed two distinctive isoforms of

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GLUT9, one is GLUT9-L and the other is GLUT9-S. GLUT9-L is located in the basolateral membrane and is responsible for the urate reabsorption. [17] Intracellular UA exhibits oxidant effect which induces inflammation further via

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stimulating the level of MCP-1, NF-κB, and NLRP3. [18, 19] UA also induces

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podocyte injury, thus promoting albuminuria.[20] In addition, UA causes renin-angiotensin-aldosterone

and

COX-2

systems

activation,

endothelial-mesenchymal transition, endothelial dysfunction and fibrosis, all contributing to chronic kidney disease (CKD). [21, 22] CKD is defined as abnormalities of kidney structure (i.e. albuminuria) or function (i.e. glomerular filtration rate [GFR] <60 mL/min/1.73m2), present for over 3 months, which is a general term for the heterogeneous disorders. [23] Conversely, the decline of GFR

ACCEPTED MANUSCRIPT could result in UA retention, forming a vicious circle of UA nephropathy. Substantial clinical data has also been exhibiting the connection between high serum UA level and CKD. Hyperuricemia is referred to elevated serum level of UA. Over-production

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and/or insufficient excretion could cause the excess burden of UA. However, there is no consensus about normal range (cut-off value) of serum level of UA. A range of 3.5 mg/dL (0.2 mmol/L) to 7.0 mg/dL (0.4 mmol/L) is often used by researchers. [24]

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Prevalence of CKD in adults with hyperuricemia is around two-to-five times higher

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than that in adults without hyperuricemia. [25] According to the work of Kawashima et al. [26], UA was a predictive factor for the new-onset CKD. Another study showed that the escalated serum level of UA increased the risk for the development of CKD. [27] Considerable studies also supported the capacity of UA in predicting the

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incidence and progression of CKD.[28, 29] Chronic hyperuricemia could result in deposition of UA crystals mainly in distal collecting ducts and the interstitium. [30] Like high serum level of UA, it is believed that the UA crystal deposition in kidney

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could evoke inflammation which leads to fibrosis, and ultimately to irreversible CKD.

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Clinical data have exhibited an association between UA crystal deposition and higher risk of CKD. [31]

[Please insert Figure 1]

2. Commercial drugs In order to lower serum level of UA, there are three targets. The first one is XOR, by inhibiting the activity of the enzyme, the production of UA decreases. Like-wise, inhibition of URAT1, the most key transporter for UA in tubular epithelium, results in

ACCEPTED MANUSCRIPT the decrement of reabsorption of UA, thus lowering its serum level. Last but not least, UA itself could be targeted. Supplement of exogenous uricase reduces UA inside human body energetically by catalyzing the oxidation of UA to allantoin.

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2.1 Allopurinol Allopurinol (1,2-dihydropyrazolo[3,4-d] pyrimidin-4-one) was first synthesized in 1956 by Roland K. Robins. [32] Later, metabolic studies of Allopurinol were

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performed in Gertrude Elion’s lab. Now, allopurinol is available all over the world. As

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an analog of the natural purine, Allopurinol is both a substrate for, and an inhibitor of, the XOR, with the Ki value of 700 nM [33]. By impeding the activity of XOR, Allopurinol reduces the generation of UA from xanthine and hypoxanthine which could be reutilized for the synthesize of nucleic acid or disposed by the kidney, thus

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not accumulating in the serum. After oral administration, Allopurinol achieves the peak plasma concentration (Cmax) within one hour and is promptly metabolized to oxypurinol, which is the active metabolite with Cmax occurring in 3-5 hours. Neither

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Allopurinol nor oxypurinol binds to plasma protein significantly. Terminal elimination

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half-life (t1/2) for oxypurinol ranges 18-40 hours, much longer than that of Allopurinol, 0.7-1.5h, which prolongs actual effective period of Allopurinol to a great extent. Oxypurinol accounts for preeminent portion of species excreted in the urine, while the amount of unchanged Allopurinol excreted was under 10% of the daily dose. [33-36] Allopurinol is generally well tolerated, nevertheless, a small number of patients, 0.1% approximately, may suffer from a life-threatening hypersensitive syndrome, also termed severe cutaneous adverse reactions, with a mortality as high as 25%. Presence

ACCEPTED MANUSCRIPT of the HLA-B*5801 allele, which is the most common in Han Chinese, Korean, and Thai descent, dramatically increases the risk of Allopurinol hypersensitivity. Another risk factor associated with developing the hypersensitivity syndrome is impairment of

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kidney. [37] Patients with severe CKD (creatinine clearance, CrCL < 10 mL/min) cannot excrete oxypurinol into urine. [38] Change of Allopurinol dosage should be considered in the condition of compromised GFR. The American College of

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Rheumatology guidelines recommends that the initial dose should be less than 100

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mg/d, and 50 mg/d for patients whose CrCL < 60 mL/min. [39] Another suggestion is 1.5 mg of Allopurinol per mL/min eGFR. [40] Despite reduction of drug dose exacerbates fail in reaching targeted serum level of UA, dose more than 300 mg/d in CKD patients is not recommended.

effects,

especially

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Co-administration of Allopurinol and cytotoxic drugs might exaggerate side bone

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depression.

In

patients

who

received

cyclophosphamide, the frequency of bone marrow depression in Allopurinol

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recipients increased by 3-fold than nonrecipients.[41] Co-administration of

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azathioprine and Allopurinol also enhances bone marrow depression.[42-44] Triple increment of cyclosporin concentration in whole blood due to Allopurinol administration has been reported.[45, 46] Efficacy of Allopurinol could be crippled by diuretics. Furosemide increases serum level of oxypurinol without decreasing level of UA. [47] Similar phenomenon was observed on hydrochlorothiazide.[48] The exact mechanism is complex and remains unclear. 2.2 Febuxostat

ACCEPTED MANUSCRIPT Febuxostat,

2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic

acid, is a puissant selective inhibitor of XOR, available in most countries. Unlike Allopurinol or oxypurinol, it is not a structural analog of natural purines. So, effect of

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Febuxostat is more accurate, not significantly interfering with other purine metabolisms. What’s more, the production of reactive oxygen species is avoided replacing Allopurinol with Febuxostat since it blocks the active pterin-molybdenum

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center of the XOR but does not determine enzyme turnover. [49] Febuxostat displays

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inhibition of both oxidase and dehydrogenase form of XOR, with Ki and Ki’ values of 0.6 and 3.1nM respectively. [50] Healthy population would absorb the majority of orally administered drug, and Cmax occurs rapidly within 1 hour. Almost all of the given Febuxostat would be bound to plasma protein, with a binding rate of 99%.

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Febuxostat is chiefly catabolized to its acyl-glucuronide metabolites and to a minor extent, to active oxidative metabolites (i.e. 67M-1, 67M-2, and 67M-4) by P450(CYP) 1A2, 2C8, and 2C9 enzymes. In plasma, predominant amount of Febuxostat keeps

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unchanged, in other words, the metabolites only exist in petty concentration. T1/2 for

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Febuxostat is around 8 hours. Through renal and biliary routes, Febuxostat is excreted approximately in urine and faces.[50-52] The most prevalent side effects of Febuxostat are liver transaminase ascent, rash,

nausea, and arthralgias. In addition, cardiovascular thromboembolic events and myopathy have been reported. [53, 54] And Febuxostat was associated with the higher all-cause mortality and cardiovascular mortality than Allopurinol. [55] Of note, there are case reports on Febuxostat hypersensitivity. [56, 57] Most of the present data

ACCEPTED MANUSCRIPT suggests that Febuxostat is not only well tolerated in patients with the moderate-to-severe kidney dysfunction, without need to change dosage in CKD patients, but also slow the progression of CKD.[53, 58-61]. Maximum approved dose

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of febuxostat is 80 mg daily (120 mg in Europe). Concomitant drugs (aspirin, angiotensin II receptor blockers, β-blockers, Irbesartan/ Losartan, Loop/thiazide diuretics, and Statins) did not affect the serum

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urate lowering efficacy. [62] But Febuxostat is contraindicated with the concomitant

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use of azathioprine, because it could increase blood plasma concentrations of azathioprine, and therefore its toxicity. [63] 2.3 Topiroxostat

Topiroxostat, 4-[5-(4-Pyridinyl)-1H-1,2,4-triazol-3-yl] pyridine-2-carbonitrile,

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has been approved in Japan exclusively in 2013. It was developed as a novel non-purine inhibitor of XOR which is unaffected by renal condition, by Fujiyakuhin Co., Ltd. Topiroxostat initially behaves as a competitive-type inhibitor with a Ki value

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of 5.7nM. [64] According to the published information, after a single oral dose of

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Topiroxostat, Cmax occurs within 1 hour, and t1/2 is around 6 hours. During the repeated oral administration, Cmax delayed a little, happening in 2 hours. The plasma protein binding of Topiroxostat is more than 98%. Topiroxostat is metabolized by oxidation and glucuronidation in the liver, thereafter, it is removed through fecal and urinary pathways. Being the same class as Allopurinol, severe cutaneous adverse events has not been reported till now. In the condition of renal impairment, the clearance of

ACCEPTED MANUSCRIPT Topiroxostat slows a bit. The company declares that any increases in the plasma metabolite concentrations are considered unlikely to affect the safety of patients with severe renal impairment. Topiroxostat was verified with free radical-scavenging

indicated by mitigation of proteinuria.

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activity. Furthermore, it was considered as an efficacious renoprotective agent, as

The usual adult initial dosage is 20 mg/dose of Topiroxostat orally administered

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twice daily in the morning and evening. Thereafter, the dose should be gradually

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increased, as needed, while monitoring blood UA levels. The usual maintenance dosage should be 60 mg/dose twice daily. The dose may be adjusted according to the patient’s condition, up to 80 mg/dose twice daily. 2.4 Probenecid

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Probenecid, 4-(dipropylsulfamoyl) benzoic acid, was the first uricosuric agent, which is a prototypical inhibitor of OATs in kidney as well as other organs. As further investigation into urate transporter in proximal tubule, it was later found that

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Probenecid is an inhibitor of UART1. But it also inhibits OAT1-4, with the Ki values

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of 12.1, 766, 9.0, and 54.9µM, respectively. [65, 66]The insufficient clinical efficacy of Probenecid in lowering urate may be due to its inhibit effects of urate secretory transporters, i.e. OAT1-3. Probenecid follows oral administration and is essentially absorbed completely postdose. Cmax occurs in 1-5 hours. A great potion, 83-95% of Probenecid is bound to plasma proteins. T1/2 for Probenecid in plasma is 4-12 hours, which is dose-dependent. Probenecid undergoes the extensive metabolism, including glucuronide conjugation and alkyl side chain oxidation, after which only 5-11% of

ACCEPTED MANUSCRIPT unchanged Probenecid is excreted in urine. The metabolites are mainly eliminated through kidney. [67-69] The American College of Rheumatology guidelines recommend Probenecid as

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the first choice of uricosuric for urate-lowering treatment (ULT) but recommend against using Probenecid in cases where the GFR is less than 50ml/min. [39]

useful for prolonging the action of captopril.[70, 71]

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2.5 Benzbromarone

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Probenecid slows down the urinary excretion of captopril significantly, which is

Benzbromarone,

(3,5-dibromo-4-hydroxyphenyl)-(2-ethyl-1-benzofuran-3-yl)methanone, lowers serum level of UA by prohibiting urate reabsorption through URAT1. But it has been

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reported that Benzbromarone also inhibits urate secretory transporter OAT3. [72] It is also considered as a weak non-competitive inhibitor of XOR. [73] Cmax occurs in 2-3 hours, which depends on the particle size of the preparation. Following absorption,

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comprehensive dehalogenation of Benzbromarone proceeds in the liver to form

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metabolites, bromobenzarone and benzarone, the latter of which is the main metabolite and possess uricosuric activity as Benzbromarone itself. More than 99% of Benzbromarone binds to plasma proteins. T1/2 for Benzbromarone is around 3 hours, while t1/2 for benzarone is 14 hours. Initial effect of Benzbromarone and subsequent effect of benzarone protract the duration of action, making a single daily administration. Both parent compound and metabolites are excreted through liver and bile. [74-76]

ACCEPTED MANUSCRIPT In some countries, Benzbromarone is withdrawn from market due to its noxious hepatic toxicity. [77] In patients with moderate-to-severe CKD, no significant change of eGFR was found after receiving monotherapy with Benzbromarone for ULT. [78]

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2.6 Lesinurad Lesinurad, is a new uricosuric drug targeting HUA, approved in 2015 in USA. It is an oral URAT1 inhibitor, and it also curbs the function of OAT4, with half maximal

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inhibitory concentrations of 7.3 and 3.7 µmol/L, respectively. [79] After a single 200

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mg dose, Cmax occurs in 1-4 hours. Absolute bioavailability is almost 100%. Lesinurad is strongly bound to plasma proteins, with a binding rate more than 98%. Cytochrome P450 (CYP) 2C9 is responsible for the oxidative metabolism of Lesinurad, and the metabolites don’t have effect on urate lowering as parent

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compound. T1/2 is approximately 5 hours, and the elimination is via both urine and bile routes. Most frequent adverse events are headache, influenza and gastrointestinal reflux disease.

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In patients with renal impairment, Cmax was approximate to healthy population,

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but with a larger AUC. Lesinurad is a feeble CYP3A inducer, while HMG-CoA reductase inhibitors which are often used by patients with CKD are sensitive CYP3A substrates, so the potential reduced efficacy should be noted. Lesinurad must be used as adjunctive therapy of HUA combined with a xanthine oxidase inhibitor, since administration alone boosts risk of acute renal failure. [79, 80] 2.7 Pegloticase Pegloticase, the only available mammalian recombinant uricase so far, which

ACCEPTED MANUSCRIPT reduces serum level of UA energetically by catalyzing the oxidation of urate to allantoin. As exogenous protein, Pegloticase should be intravenously administered. Adding the inert polymer polyethylene glycol to the protein bestows extension of t1/2

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of the active enzyme to 6.4-13.8 days and subsidence of patients’ immune recognition. Nonetheless, the infusion-related reactions including drug immunogenicity has been reported in up to 25-50% of patients, which limits its utilization. Creatinine clearance

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did not affect the pharmacokinetics of Pegloticase, and treatment of Pegloticase did

81, 82] 2.8 Efficacy comparison

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not impact eGFR in patients with CKD. The approved dose is 8mg every 2 weeks. [77,

Allopurinol has been recommended for the first-line ULT for a long time.

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However, with the most commonly dose of 300 mg/d of Allopurinol, more than 50% patients failed achieving expected urate reduction. [83] There are three approaches to gain further decrement of UA in serum, the first of which is to use higher dose of

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Allopurinol, more than 300 mg/L, which is prohibited in patients with CKD. Other

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approaches are to replace Allopurinol with a novel XOI, or to co-prescribe with an adjunctive agent, usually one of the uricosurics. In

Allopurinol-refractory

hyperuricemic

patients,

Febuxostat

effectively

decreased serum level of UA and was well tolerated.[84] A similar trial was also carried out in Japan, in which patients with advanced renal impairment (eGFR < 30 mL/min/1.73m2) who failed to achieve targeted serum level of UA by treatment of Allopurinol responded to Febuxostat treatment effectively, as indicated by reduced

ACCEPTED MANUSCRIPT serum level of UA and suppressed progressive decline of kidney function.[85] In Chinese Han hyperuricemic patients with the moderate-to-severe renal impairment (CKD stages 3-5), Febuxostat displayed higher urate-lowering efficacy than

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Allopurinol, and the decrement of serum level of UA contributed to a slower progression of CKD,[86] consistent with the cohort study carried out in Japan.[87] A 13-year cohort study performed in Taiwan demonstrated that Febuxostat and

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Benzbromarone (alone administration) were more efficacious both in lowering serum

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level of UA and retarding the progression of CKD compared with Allopurinol.[88] Febuxostat has also been reported to be more renoprotective (i.e. improving albuminuria) than Allopurinol.[89, 90] Nonetheless, Allopurinol was associated with lower incidence of renal disease in old hyperuricemic patients than Febuxostat.[91]

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Topiroxostat 120mg/d didn’t exhibit superior reduction of serum level of UA versus Allopurinol 200mg/d but was well tolerated. [92] A study on mice demonstrated that Febuxostat diminished urate in the liver and kidney more

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efficacious than Topiroxostat, while the serum level of UA of the Topiroxostat-treated

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group was lower than that in the Febuxostat-treated group. And the potent inhibition of serum XOR activity of Topiroxostat may contribute to its effect on reduced urinary albumin excretion. [93] Notwithstanding, another trail on human patients showed that effects

of

Febuxostat

on

serum

level

of

UA reduction,

anti-oxidation,

anti-inflammation, reno-protection were more marked and more rapid than that of Topiroxostat. After longer treatment, the two agents received similar effects. [94] Uricosurics own certain shortcomings, including limited utilization in case of

ACCEPTED MANUSCRIPT renal diseases, which are common in patients who failed to respond to allopurinol, and risk of induced kidney stone related to higher concentration of UA in urine. [77] Combination of Lesinurad and Allopurinol increased the percentage of patients

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who achieved serum level of UA targets (serum level of UA< 6 mg/dL). Lesinurad at dose of 200 mg and 400 mg was tested. And it turned out that the larger dose, 400mg, had a better efficacy. However, as the dose increased, treatment-emergent adverse

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events happened on more patients, including severe and fatal adverse events. Base on

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the findings, Lesinurad 200 mg added to Allopurinol manifests superior serum level of UA lowering versus Allopurinol-alone with well toleration in patients. [95-97] Addition of Probenecid enhanced urate lowering effect of Allopurinol dose-dependently, while less effective in patients with renal impairment. [98] And in a

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large cohort study, Probenecid appeared to moderately decrease risk of cardiovascular events (e.g. myocardial infarction, stroke, heart failure deterioration) compared with Allopurinol. [99]

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There was a successful case of combination of Probenecid and Febuxostat, in

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which the patients had CKD with eGFR at 37 ml/min and serum level of UA at 11 mg/dL in spite of maximal dosage of Febuxostat. Treatment of Pegloticase also failed. Following addition of Probenecid, serum level of UA of the patients declined dramatically to be lower than 6 mg/dL. [100] In addition to the commercial drugs, there are more novel agents at various stages of development currently. [Please insert Table 1] 3. Pipeline agents

ACCEPTED MANUSCRIPT LC350189 is a novel selective xanthine oxidase inhibitor. It was well-tolerated in the dose range of 10-800 mg in healthy subjects and showed substantial efficacy for ULT. It is expected that LC350189 could be safe and efficacious in patients with

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hyperuricemia. [101] But the results still have not been updated. Merbarone (RLBN1001) was designed to treat for cancer but found to have the urate lowering effects due to the inhibition of URAT1 and to a lesser extent the

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inhibition of XOR. But there is no clinical trial ongoing.

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The uricosuric agents (Arhalofenate, Verinurad, Levotofisopam, UR-1102, Dotinurad, and SHR4640) share similar mechanism, inhibiting organic ion transporters in the proximal tubule, especially URAT1, but maybe also interacting with OATs. Among other ULTs, Verinurad seems to be the most promising. [102]

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SEL-037 (Pegsiticase) is a modified pegylated recombinant uricase. Adding the inert polymer polyethylene glycol to the protein bestows extension of t1/2 of the active enzyme to 6.4-13.8 days and subsidence of patients’ immune recognition. [103]

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SEL-212, combination of uricase and rapamycin are designed to enhance efficacy of

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UA lowering via selective attenuation of anti-drug antibodies against uricase. [104] As mentioned above, there should be more targets throughout UA metabolic

pathway beyond xanthine oxidase inhibitors, uricosurics, and uricase. Ulodesine (BCX4208) is the only drug under study that inhibits purine nucleoside phosphorylase, with Ki value of 1.1 nM. [105] Despite decrease of hypoxanthine and xanthine levels, Ulodesine exhibited little efficacy on UA itself. [77] [Please insert Table 2]

ACCEPTED MANUSCRIPT 4. Natural flavonoid Innumerable flavonoids emerge as urate-lowering and disease-modifying agents. As XOR inhibitors and/or uricosurics, these phytochemicals also exhibit effects of

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anti-oxidant, anti-inflammation, and anti-fibrosis, which are protective for renal function. Significant effect on urate lowering was observed in vivo, albeit, the studies were small-scaled and limited on mice model, except one that tested quercetin on

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male population with pre-hyperuricemia (serum level of UA>300 µmol/L without

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gout).[106] Table.3 summarized the characteristics of 12 flavonoids which were studied in hyperuricemia-induced nephropathy.[107-126] Among the above phytochemicals, Baicalin, Kaempferol, Luteolin, Morin, and Quercetin underwent extensive study on chemical properties. Baicalein inhibits XOR with Kd value of

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67.49 µM. Kaempferol, Luteolin, and Quercetin are also XOR inhibitors with Ki values of 6.77, 2.38, and 0.472 µM, respectively. Morin exhibits dual inhibition effects, with Ki values of 7.9 µM for XOR and 5.74 µM for URAT1. According to the

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work of S. F. Mo et, [127] kaempferol exhibited the most excellent hypouricemic

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effect. The effects of morin and quercetin were also significant while luteolin presented a lower efficacy and baicalin didn’t decrease SUA significantly. Analysis of the hypouricemic effects and structure of these flavonoids indicated that removal of the 3-hydroxyl group (luteolin) diminished urate-lowering effects. Further, absence of 4-hydroxyl group (baicalin) might inactivate the hypouricemic effect. However, baicalein, which owns almost the same structure as baicalin except the 7th substituent position, 7-hydroxyl group instead of O-GlcA, showed significant hypouricemic

ACCEPTED MANUSCRIPT effects. [110] F. Haidari et. also proved that kaempferol had a stronger hypouricemic effects than quercetin. [128] Y. Lin et. Showed that luteolin had a potent hypouricemic effects which was even stronger than allopurinol. [113] Luteolin exhibited a stronger

[Please insert Table 3]

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5. Conclusion

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synergistic effect with kaempferol at the lower concentration. [111]

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In summary, it is necessary for nephrologist to be aware of the intricate relationships between uric acid and CKD and master the urate-lowering treatment in the condition of CKD. Given the compromised function of kidney, via which excreted the metabolites of drugs, agents of urate-lowering treatment may require the dose

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adjustments according to creatinine clearance rate. Equally important, these agents have drug-drug interactions with other management for CKD that might intensify side

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effects. Understanding pharmacologic characteristics of urate-lowering treatment is essential in the context.

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Conflict of Interest

The authors confirm that there are no conflicts of interest.

Acknowledgement

This work was supported by Key R&D Program of Sichuan Province (2018FZ0104) and Innovation Program of Sichuan University (2018SCUH0077). Reference

ACCEPTED MANUSCRIPT [1]A. V. Yeldandi, X. D. Wang, K. Alvares, S. Kumar, M. S. Rao,J. K. Reddy, Human urate oxidase gene: cloning and partial sequence analysis reveal a stop codon within the fifth exon, Biochem. Biophys. Res. Commun. 171 (1990) 641-646. doi:

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10.1016/0006-291X(90)91194-W [2]P. Pacher, A. Nivorozhkin,C. Szabo, Therapeutic effects of xanthine oxidase

Rev. 58 (2006) 87-114. doi: 10.1124/pr.58.1.6

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inhibitors: renaissance half a century after the discovery of allopurinol, Pharmacol

M AN U

[3]K. Ichida, H. Matsuo, T. Takada, A. Nakayama, K. Murakami, T. Shimizu, Y. Yamanashi, H. Kasuga, H. Nakashima, T. Nakamura, Y. Takada, Y. Kawamura, H. Inoue, C. Okada, Y. Utsumi, Y. Ikebuchi, K. Ito, M. Nakamura, Y. Shinohara, M. Hosoyamada, Y. Sakurai, N. Shinomiya, T. Hosoya,H. Suzuki, Decreased extra-renal

10.1038/ncomms1756

TE D

urate excretion is a common cause of hyperuricemia, Nat. Commun. 3 (2012) 764. doi:

[4]D. B. Mount, The kidney in hyperuricemia and gout, Curr. Opin. Nephrol.

EP

Hypertens. 22 (2013) 216-223. doi: 10.1097/MNH.0b013e32835ddad2

AC C

[5]O. M. Woodward, A. Köttgen, J. Coresh, E. Boerwinkle, W. B. Guggino,M. Köttgen, Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout, Proc. Natl. Acad. Sci. 106 (2009) 10338-10342. doi: 10.1073/pnas.0901249106 [6]R. A. Van Aubel, P. H. Smeets, J. J. van den Heuvel,F. G. Russel, Human organic anion transporter MRP4 (ABCC4) is an efflux pump for the purine end metabolite urate with multiple allosteric substrate binding sites, Am J Physiol Renal Physiol. 288

ACCEPTED MANUSCRIPT (2005) F327-333. doi: 10.1152/ajprenal.00133.2004 [7]R. J. Reimer,R. H. Edwards, Organic anion transport is the primary function of the SLC17/type I phosphate transporter family, Pflügers Archiv. 447 (2004) 629-635. doi:

RI PT

10.1007/s00424-003-1087-y [8]T. Chiba, H. Matsuo, Y. Kawamura, S. Nagamori, T. Nishiyama, L. Wei, A. Nakayama, T. Nakamura, M. Sakiyama, T. Takada, Y. Taketani, S. Suma, M. Naito, T.

SC

Oda, H. Kumagai, Y. Moriyama, K. Ichida, T. Shimizu, Y. Kanai,N. Shinomiya,

M AN U

NPT1/SLC17A1 is a renal urate exporter in humans and its common gain-of-function variant decreases the risk of renal underexcretion gout, Arthritis Rheumatol. 67 (2015) 281-287. doi: 10.1002/art.38884

[9]P. Jutabha, N. Anzai, K. Kitamura, A. Taniguchi, S. Kaneko, K. Yan, H. Yamada, H.

TE D

Shimada, T. Kimura, T. Katada, T. Fukutomi, K. Tomita, W. Urano, H. Yamanaka, G. Seki, T. Fujita, Y. Moriyama, A. Yamada, S. Uchida, M. F. Wempe, H. Endou,H. Sakurai, Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common

EP

renal secretory pathway for drugs and urate, J Biol. Chem. 285 (2010) 35123-35132.

AC C

doi: 10.1074/jbc.M110.121301

[10]T. Sekine, S. H. Cha,H. J. P. A. Endou, The multispecific organic anion transporter

(OAT)

family,

Pflügers

Archiv.

440

(2000)

337-350.

doi:

10.1007/s004240000297 [11]N. Bakhiya, A. Bahn, G. Burckhardt, N. A. Wolff, Human Organic Anion Transporter 3 (hOAT3) can Operate as an Exchanger and Mediate Secretory Urate Flux, Cell. Physiol. Biochem. 13 (2003) 249-256. doi: 10.1159/000074539

ACCEPTED MANUSCRIPT [12]M. Sato, H. Mamada, N. Anzai, Y. Shirasaka, T. Nakanishi,I. Tamai, Renal Secretion of Uric Acid by Organic Anion Transporter 2 (OAT2/SLC22A7) in Human, Biol. Pharm. Bull. 33 (2010) 498-503. doi: 10.1248/bpb.33.498

RI PT

[13]M. Sakiyama, H. Matsuo, S. Shimizu, H. Nakashima, A. Nakayama, T. Chiba, M. Naito, T. Takada, H. Suzuki, N. Hamajima, K. Ichida, T. Shimizu,N. Shinomiya, A Common Variant of Organic Anion Transporter 4 (OAT4/SLC22A11) Gene Is

SC

Associated with Renal Underexcretion Type Gout, Drug Metab. Pharmacokinet. 29

M AN U

(2014) 208-210. doi: 10.2133/dmpk.DMPK-13-NT-070

[14]A. Bahn, Y. Hagos, S. Reuter, D. Balen, H. Brzica, W. Krick, B. C. Burckhardt, I. Sabolic,G. Burckhardt, Identification of a new urate and high affinity nicotinate transporter, hOAT10 (SLC22A13), J Biol. Chem. 283 (2008) 16332-16341. doi:

TE D

10.1074/jbc.M800737200

[15]A. Enomoto, H. Kimura, A. Chairoungdua, Y. Shigeta, P. Jutabha, S. Ho Cha, M. Hosoyamada, M. Takeda, T. Sekine, T. Igarashi, H. Matsuo, Y. Kikuchi, T. Oda, K.

EP

Ichida, T. Hosoya, K. Shimokata, T. Niwa, Y. Kanai,H. Endou, Molecular

AC C

identification of a renal urate–anion exchanger that regulates blood urate levels, Nature. 417 (2002) 447. doi: 10.1038/nature742 [16]V. Vitart, I. Rudan, C. Hayward, N. K. Gray, J. Floyd, C. N. A. Palmer, S. A. Knott, I. Kolcic, O. Polasek, J. Graessler, J. F. Wilson, A. Marinaki, P. L. Riches, X. Shu, B. Janicijevic, N. Smolej-Narancic, B. Gorgoni, J. Morgan, S. Campbell, Z. Biloglav, L. Barac-Lauc, M. Pericic, I. M. Klaric, L. Zgaga, T. Skaric-Juric, S. H. Wild, W. A. Richardson, P. Hohenstein, C. H. Kimber, A. Tenesa, L. A. Donnelly, L.

ACCEPTED MANUSCRIPT D. Fairbanks, M. Aringer, P. M. McKeigue, S. H. Ralston, A. D. Morris, P. Rudan, N. D. Hastie, H. Campbell,A. F. Wright, SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout, Nat. Genet. 40 (2008)

RI PT

437. doi: 10.1038/ng.106 [17]T. Kimura, M. Takahashi, K. Yan,H. Sakurai, Expression of SLC2A9 isoforms in

e84996. doi: 10.1371/journal.pone.0084996

SC

the kidney and their localization in polarized epithelial cells, PLoS One. 9 (2014)

M AN U

[18]Y. Zhou, L. Fang, L. Jiang, P. Wen, H. Cao, W. He, C. Dai,J. Yang, Uric acid induces renal inflammation via activating tubular NF-kappaB signaling pathway, PloS one. 7 (2012) e39738. doi: 10.1371/journal.pone.0039738

[19]T. T. Braga, M. F. Forni, M. Correa-Costa, R. N. Ramos, J. A. Barbuto, P. Branco,

TE D

A. Castoldi, M. I. Hiyane, M. R. Davanso, E. Latz, B. S. Franklin, A. J. Kowaltowski,N. O. Camara, Soluble Uric Acid Activates the NLRP3 Inflammasome, Sci. Rep. 7 (2017) 39884. doi: 10.1038/srep39884

EP

[20]S. Asakawa, S. Shibata, C. Morimoto, T. Shiraishi, T. Nakamura, Y. Tamura, T.

AC C

Kumagai, M. Hosoyamada,S. Uchida, Podocyte Injury and Albuminuria in Experimental Hyperuricemic Model Rats, Oxid. Med. Cell. Longev. 2017 (2017) 3759153. doi: 10.1155/2017/3759153 [21]I. Y. Kim, D. W. Lee, S. B. Lee,I. S. Kwak, The role of uric acid in kidney fibrosis: experimental evidences for the causal relationship, BioMed Res. Int. 2014 (2014) 638732. doi: 10.1155/2014/638732 [22]D. H. Kang, T. Nakagawa, L. Feng, S. Watanabe, L. Han, M. Mazzali, L. Truong,

ACCEPTED MANUSCRIPT R. Harris,R. J. Johnson, A role for uric acid in the progression of renal disease, J Am Soc Nephrol. 13 (2002) 2888-2897. doi: 10.1097/01.ASN.0000034910.58454.FD [23]A. S. Levey,J. Coresh, Chronic kidney disease, Lancet 379 (2012) 165-180. doi:

RI PT

10.1016/S0140-6736(11)60178-5 [24]D. Gustafsson,R. Unwin, The pathophysiology of hyperuricaemia and its possible

(2013) 164. doi: 10.1186/1471-2369-14-164

SC

relationship to cardiovascular disease, morbidity and mortality, BMC Nephrol. 14

M AN U

[25]Y. Zhu, B. J. Pandya,H. K. Choi, Comorbidities of Gout and Hyperuricemia in the US General Population: NHANES 2007-2008, Am J Med. 125 (2012) 679-687.e671. doi: 10.1016/j.amjmed.2011.09.033

[26]M. Kawashima, K. Wada, H. Ohta, H. Terawaki,Y. Aizawa, Association between

TE D

asymptomatic hyperuricemia and new-onset chronic kidney disease in Japanese male workers: a long-term retrospective cohort study, BMC Nephrol. 12 (2011) 31. doi: 10.1186/1471-2369-12-31

EP

[27]L. Li, C. Yang, Y. Zhao, X. Zeng, F. Liu,P. Fu, Is hyperuricemia an independent

AC C

risk factor for new-onset chronic kidney disease?: A systematic review and meta-analysis based on observational cohort studies, BMC Nephrol. 15 (2014) 122. doi: 10.1186/1471-2369-15-122 [28]K. Iseki, Significance of Hyperuricemia among Community-Based Screening Participants, Contrib. Nephrol. 192 (2018) 41-47. doi: 10.1159/000484277 [29]G. X. Li, X. H. Jiao,X. B. Cheng, Correlations between blood uric acid and the incidence and progression of type 2 diabetes nephropathy, Eur Rev Med Pharmacol

ACCEPTED MANUSCRIPT Sci. 22 (2018) 506-511. doi: 10.26355/eurrev_201801_14202 [30]D. Abramowicz, P. Cochat, F. H. Claas, U. Heemann, J. Pascual, C. Dudley, P. Harden, M. Hourmant, U. Maggiore, M. Salvadori, G. Spasovski, J. P. Squifflet, J.

RI PT

Steiger, A. Torres, O. Viklicky, M. Zeier, R. Vanholder, W. Van Biesen,E. Nagler, European Renal Best Practice Guideline on kidney donor and recipient evaluation and perioperative care, Nephrol. Dial. Transplant. 30 (2015) 1790-1797. doi:

SC

10.1093/ndt/gfu216

M AN U

[31]C. C. Li, T. M. Chien, W. J. Wu, C. N. Huang,Y. H. Chou, Uric acid stones increase the risk of chronic kidney disease, Urolithiasis. 46 (2018) 543-547. doi: 10.1007/s00240-018-1050-1

[32]R. K. Robins, Potential Purine Antagonists. I. Synthesis of Some 4,6-Substituted

10.1021/ja01585a023

TE D

Pyrazolo [3,4-d] pyrimidines1, J. Am. Chem. Soc. 78 (1956) 784-790. doi:

[33]G. B. Elion, A. Kovensky,G. H. Hitchings, Metabolic studies of allopurinol, an

EP

inhibitor of xanthine oxidase, Biochem. Pharmacol. 15 (1966) 863-880. doi:

AC C

10.1016/0006-2952(66)90163-8 [34]G. B. Elion, The purine path to chemotherapy, Science. 244 (1989) 41-47. doi: 10.1126/science.2649979 [35]G. B. Elion, T. a.-F. Yü, A. B. Gutman,G. H. Hitchings, Renal clearance of oxipurinol, the chief metabolite of allopurinol, Am. J. Med. 45 (1968) 69-77. doi: 10.1016/0002-9343(68)90008-9 [36]F. Pea, Pharmacology of drugs for hyperuricemia. Mechanisms, kinetics and

ACCEPTED MANUSCRIPT interactions, Contrib. Nephrol. 147 (2005) 35-46. doi: 10.1159/000082540 [37]C. Quach,B. T. Galen, HLA-B*5801 Testing to Prevent Allopurinol Hypersensitivity Syndrome: A Teachable Moment, JAMA Intern Med. 178 (2018)

RI PT

1260-1261. doi: 10.1001/jamainternmed.2018.3556 [38]L. K. Stamp, P. T. Chapman,S. C. Palmer, Allopurinol and kidney function: An update, Joint Bone Spine. 83 (2016) 19-24. doi: 10.1016/j.jbspin.2015.03.013

SC

[39]D. Khanna, J. D. Fitzgerald, P. P. Khanna, S. Bae, M. K. Singh, T. Neogi, M. H.

M AN U

Pillinger, J. Merill, S. Lee, S. Prakash, M. Kaldas, M. Gogia, F. Perez-Ruiz, W. Taylor, F. Liote, H. Choi, J. A. Singh, N. Dalbeth, S. Kaplan, V. Niyyar, D. Jones, S. A. Yarows, B. Roessler, G. Kerr, C. King, G. Levy, D. E. Furst, N. L. Edwards, B. Mandell, H. R. Schumacher, M. Robbins, N. Wenger, R. Terkeltaub,R. American

TE D

College of, 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia, Arthritis Care Res. 64 (2012) 1431-1446. doi: 10.1002/acr.21772

EP

[40]L. K. Stamp, W. J. Taylor, P. B. Jones, J. L. Dockerty, J. Drake, C. Frampton,N.

AC C

Dalbeth, Starting dose is a risk factor for allopurinol hypersensitivity syndrome: a proposed safe starting dose of allopurinol, Arthritis Rheum. 64 (2012) 2529-2536. doi: 10.1002/art.34488

[41]Allopurinol and cytotoxic drugs. Interaction in relation to bone marrow depression. Boston Collaborative Drug Surveillance Program, JAMA. 227 (1974) 1036-1040. doi: 10.1001/jama.1974.03230220026008 [42]R. B. Gearry, A. S. Day, M. L. Barclay, R. W. Leong,M. P. Sparrow, Azathioprine

ACCEPTED MANUSCRIPT and allopurinol: A two-edged interaction, J. Gastroentero. Hepatol. 25 (2010) 653-655. doi: 10.1111/j.1440-1746.2010.06254.x [43]D. T. Kennedy, M. S. Hayney,K. D. Lake, Azathioprine and allopurinol: the price

RI PT

of an avoidable drug interaction, Ann. Pharmacother. 30 (1996) 951-954. doi: 10.1177/106002809603000906

[44]M. Millan, M. Castro-Fernandez, J. Ampuero,M. Romero-Gomez, Myelotoxicity

Gastroenterol.

Hepatol.

10.1016/j.gastrohep.2012.10.002

36

(2013)

298-299.

doi:

M AN U

disease,

SC

due to interaction between azathioprine and allopurinol in a patient with Crohn's

[45]M. Gorrie, M. Beaman, A. Nicholls,P. Backwell, Allopurinol interaction with cyclosporin, Brit Med J 308 (1994) 113. doi: 10.1136/bmj.308.6921.113c

TE D

[46]S. L. Stevens, M. H. Goldman, Cyclosporine toxicity associated with allopurinol, South. Med. J. 85 (1992) 1265-1266. doi: 10.1097/00007611-199212000-00032 [47]L. K. Stamp, M. L. Barclay, J. L. O'Donnell, M. Zhang, J. Drake, C. Frampton,P.

EP

T. Chapman, Furosemide increases plasma oxypurinol without lowering serum

AC C

urate--a complex drug interaction: implications for clinical practice, Rheumatology 51 (2012) 1670-1676. doi: 10.1093/rheumatology/kes091 [48]K. R. Hande, Evaluation of a thiazide-allopurinol drug interaction, Am. J. Med. Sci. 292 (1986) 213-216. doi: 10.1097/00000441-198610000-00006 [49]M. Bove, A. F. Cicero, M. Veronesi,C. Borghi, An evidence-based review on urate-lowering hyperuricemia,

treatments: Vasc

implications

Health

Risk

for

optimal

Manag.

13

treatment (2017)

of

chronic

23-28.

doi:

ACCEPTED MANUSCRIPT 10.2147/VHRM.S115080 [50]Y. Takano, K. Hase-Aoki, H. Horiuchi, L. Zhao, Y. Kasahara, S. Kondo,M. A. Becker, Selectivity of febuxostat, a novel non-purine inhibitor of xanthine dehydrogenase,

Life

Sci.

76

(2005)

1835-1847.

doi:

RI PT

oxidase/xanthine

10.1016/j.lfs.2004.10.031

[51]B. A. Grabowski, R. Khosravan, L. Vernillet,D. J. Mulford, Metabolism and

SC

excretion of [14C] febuxostat, a novel nonpurine selective inhibitor of xanthine

M AN U

oxidase, in healthy male subjects, J Clin. Pharmacol. 51 (2011) 189-201. doi: 10.1177/0091270010365549

[52]M. D. Mayer, R. Khosravan, L. Vernillet, J. T. Wu, N. Joseph-Ridge,D. J. Mulford, Pharmacokinetics and pharmacodynamics of febuxostat, a new non-purine selective

TE D

inhibitor of xanthine oxidase in subjects with renal impairment, Am J Ther. 12 (2005) 22-34. doi: 10.1097/00045391-200501000-00005 [53]B. L. Love, R. Barrons, A. Veverka,K. M. Snider, Urate-lowering therapy for gout: on

febuxostat,

Pharmacotherapy

EP

focus

30

(2010)

594-608.

doi:

AC C

10.1592/phco.30.6.594

[54]C. T. Liu, C. Y. Chen, C. Y. Hsu, P. H. Huang, F. Y. Lin, J. W. Chen,S. J. Lin, Risk of Febuxostat-Associated Myopathy in Patients with CKD, Clin J. Am. Soc. Nephrol. 12 (2017) 744-750. doi: 10.2215/CJN.08280816 [55]W. B. White, K. G. Saag, M. A. Becker, J. S. Borer, P. B. Gorelick, A. Whelton, B. Hunt, M. Castillo,L. Gunawardhana, Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout, N Engl J Med 378 (2018) 1200-1210. doi:

ACCEPTED MANUSCRIPT 10.1056/NEJMoa1710895 [56]E. Paschou, E. Gavriilaki, G. Papaioannou, A. Tsompanakou, A. Kalaitzoglou,N. Sabanis, Febuxostat hypersensitivity: another cause of DRESS syndrome in chronic

RI PT

kidney disease?, Eur Ann Allergy Clin Immunol. 48 (2016) 251-255. doi: [57]Y. H. Lien,J. L. Logan, Cross-Reactions Between Allopurinol and Febuxostat, Am J Med. 130 (2017) e67-e68. doi: 10.1016/j.amjmed.2016.08.042

SC

[58]X. X. Zeng, Y. Tang, K. Hu, X. Zhou, J. Wang, L. Zhu, J. Liu,J. Xu, Efficacy of

M AN U

febuxostat in hyperuricemic patients with mild-to-moderate chronic kidney disease: a meta-analysis of randomized clinical trials: A PRISMA-compliant article, Medicine (Baltimore) 97 (2018) e0161. doi: 10.1097/MD.0000000000010161 [59]Y. Shibagaki, I. Ohno, T. Hosoya,K. Kimura, Safety, efficacy and renal effect of

TE D

febuxostat in patients with moderate-to-severe kidney dysfunction, Hypertens. Res. 37 (2014) 919-925. doi: 10.1038/hr.2014.107 [60]X. Liu, K. Liu, Q. Sun, Y. Wang, J. Meng, Z. Xu,Z. Shi, Efficacy and safety of

EP

febuxostat for treating hyperuricemia in patients with chronic kidney disease and in

AC C

renal transplant recipients: A systematic review and meta-analysis, Exp. Ther. Med. 16 (2018) 1859-1865. doi: 10.3892/etm.2018.6367 [61]D. H. Lim, J. S. Oh, S. M. Ahn, S. Hong, Y. G. Kim, C. K. Lee, S. W. Choi,B. Yoo, Febuxostat in Hyperuricemic Patients With Advanced CKD, Am J Kidney Dis. 68 (2016) 819-821. doi: 10.1053/j.ajkd.2016.07.001 [62]H. Koide, D. Hira, M. Tsujimoto, Y. Katsube, T. Minegaki, T. Uzu, Y. Ikeda, S. Y. Morita, K. Nishiguchi,T. Terada, Previous Dosage of Allopurinol Is a Strong

ACCEPTED MANUSCRIPT Determinant of Febuxostat Efficacy, Biol. Pharm. Bull. 40 (2017) 681-686. doi: 10.1248/bpb.b16-00972 [63]C. C. Coss, A. Jones,J. T. Dalton, Pharmacokinetic drug interactions of the

RI PT

selective androgen receptor modulator GTx-024(Enobosarm) with itraconazole, rifampin, probenecid, celecoxib and rosuvastatin, Invest. New Drugs. 34 (2016) 458-467. doi: 10.1007/s10637-016-0353-8

SC

[64]K. Matsumoto, K. Okamoto, N. Ashizawa,T. Nishino, FYX-051: A Novel and

M AN U

Potent Hybrid-Type Inhibitor of Xanthine Oxidoreductase, J.Pharmacol. Exp. Ther. 336 (2011) 95. doi: 10.1124/jpet.110.174540

[65]A. Enomoto, M. Takeda, M. Shimoda, S. Narikawa, Y. Kobayashi, Y. Kobayashi, T. Yamamoto, T. Sekine, S. H. Cha, T. Niwa,H. Endou, Interaction of Human Organic

TE D

Anion Transporters 2 and 4 with Organic Anion Transport Inhibitors, J.Pharmacol. Exp. Ther. 301 (2002) 797. doi: 10.1124/jpet.301.3.797 [66]M. Takeda, S. Narikawa, M. Hosoyamada, S. Ho Cha, T. Sekine,H. Endou,

EP

Characterization of organic anion transport inhibitors using cells stably expressing

AC C

human organic anion transporters, Eur. J. Pharmacol. 419 (2001) 113-120. doi: 10.1016/S0014-2999(01)00962-1 [67]R. F. Cunningham, Z. H. Israili,P. G. J. C. P. Dayton, Clinical Pharmacokinetics of

Probenecid,

Clin.

Pharmacokinet.

6

(1981)

135-151.

doi:

10.2165/00003088-198106020-00004 [68]Z. H. Israili, J. M. Percel, R. F. Cunningham, P. G. Dayton, T. F. Yu, A. B. Gutman, K. R. Long, R. C. Long, Jr.,J. H. Goldstein, Metabolites of probenecid.

ACCEPTED MANUSCRIPT Chemical, physical, and pharmacological studies, J. Med. Chem. 15 (1972) 709-713. doi: 10.1021/jm00277a004 [69]A. Selen, G. L. Amidon,P. G. Welling, Pharmacokinetics of probenecid following

RI PT

oral doses to human volunteers, J Pharm Sci. 71 (1982) 1238-1242. doi: 10.1002/jps.2600711114

[70]O. H. Drummer, J. Thompson, R. Hooper,B. Jarrott, Effect of probenecid on the

M AN U

3347-3351. doi: 10.1061/0006-2952(85)90356-9

SC

disposition of captopril and captopril dimer in the rat, Biochem. Pharmacol. 34 (1985)

[71]S. M. Sinhvi, K. L. Duchin, D. A. Willard, D. N. McKinstry,B. H. Migdalof, Renal handling of captopril: effect of probenecid, Clin. Pharmacol. Ther. 32 (1982) 182-189. doi: 10.1038/clpt.1982.145

TE D

[72]S. O. Ahn, S. Ohtomo, J. Kiyokawa, T. Nakagawa, M. Yamane, K. J. Lee, K. H. Kim, B. H. Kim, J. Tanaka, Y. Kawabe,N. Horiba, Stronger Uricosuric Effects of the Novel Selective URAT1 Inhibitor UR-1102 Lowered Plasma Urate in Tufted

EP

Capuchin Monkeys to a Greater Extent than Benzbromarone, J. Pharmacol. Exp. Ther.

AC C

357 (2016) 157. doi: 10.1124/jpet.115.231647 [73]D. S. Sinclair,I. H. Fox, The pharmacology of hypouricemic effect of benzbromarone, J Rheumatol. 2 (1975) 437-445. [74]H. Ferber, H. Vergin,G. J. E. J. o. C. P. Hitzenberger, Pharmacokinetics and biotransformation of benzbromarone in man, Eur. J. Clin. Pharmacol. 19 (1981) 431-435. doi: 10.1007/bf00548587 [75]R. C. Heel, R. N. Brogden, T. M. Speight,G. S. J. D. Avery, Benzbromarone: A

ACCEPTED MANUSCRIPT Review of its Pharmacological Properties and Therapeutic Use in Gout and Hyperuricaemia,

Drugs.

14

(1977)

349-366.

doi:

10.2165/00003495-197714050-00002

RI PT

[76]I. Walter-Sack, J. X. de Vries, A. Ittensohn, M. Kohlmeier,E. J. K. W. Weber, Benzbromarone disposition and uricosuric action; evidence for hydroxilation instead of debromination to benzarone, Klin Wochenschr. 66 (1988) 160-166. doi:

SC

10.1007/bf01727785

M AN U

[77]T. Pascart,P. Richette, Investigational drugs for hyperuricemia, an update on recent developments, Expert Opin. Investig. Drugs. 27 (2018) 437-444. doi: 10.1080/13543784.2018.1471133

[78]S. Fujimori, K. Ooyama, H. Ooyama,H. Moromizato, Efficacy of benzbromarone

Nucleotides

TE D

in hyperuricemic patients associated with chronic kidney disease, Nucleosides, Nucleic

acids.

30

(2011)

1035-1038.

doi:

10.1080/15257770.2011.622732

EP

[79]S. M. J. D. Hoy, Lesinurad: First Global Approval, Drugs. 76 (2016) 509-516. doi:

AC C

10.1007/s40265-016-0550-y

[80]A. K. Tausche, R. Alten, N. Dalbeth, J. Kopicko, M. Fung, S. Adler, N. Bhakta, C. Storgard, S. Baumgartner,K. Saag, Lesinurad monotherapy in gout patients intolerant to a xanthine oxidase inhibitor: a 6 month phase 3 clinical trial and extension study, Rheumatology. 56 (2017) 2170-2178. doi: 10.1093/rheumatology/kex350 [81]J. A. Shannon,S. W. Cole, Pegloticase: A Novel Agent for Treatment-Refractory Gout, Ann. Pharmacother. 46 (2012) 368-376. doi: 10.1345/aph.1Q593

ACCEPTED MANUSCRIPT [82]R. A. Yood, F. D. Ottery, W. Irish,M. Wolfson, Effect of pegloticase on renal function in patients with chronic kidney disease: a post hoc subgroup analysis of 2 randomized, placebo-controlled, phase 3 clinical trials, BMC Res Notes. 7 (2014) 54.

RI PT

doi: 10.1186/1756-0500-7-54 [83]A. Waller,K. M. Jordan, Use of febuxostat in the management of gout in the United Kingdom, Ther. Adv. Musculoskelet. Dis. 9 (2017) 55-64. doi:

SC

10.1177/1759720x16682010

M AN U

[84]C. H. Kwak, M. Sohn, N. Han, Y. S. Cho, Y. S. Kim,J. M. Oh, Effectiveness of febuxostat in patients with allopurinol-refractory hyperuricemic chronic kidney disease, Int. J. Clin. Pharmacol. Ther. 56 (2018) 321-327. doi: 10.5414/cp202735 [85]Y. Sakai, T. Otsuka, D. Ohno, T. Murasawa, N. Sato,S. Tsuruoka, Febuxostat for

TE D

treating allopurinol-resistant hyperuricemia in patients with chronic kidney disease, Ren Fail. 36 (2014) 225-231. doi: 10.3109/0886022x.2013.844622 [86]X. Liu, H. Wang, R. Ma, L. Shao, W. Zhang, W. Jiang, C. Luo, T. Zhai,Y. Xu, The

EP

urate-lowering efficacy and safety of febuxostat versus allopurinol in Chinese patients

AC C

with asymptomatic hyperuricemia and with chronic kidney disease stages 3-5, Clin Exp Nephrol. (2018). doi: 10.1007/s10157-018-1652-5 [87]Y. Tsuruta, T. Mochizuki, T. Moriyama, M. Itabashi, T. Takei, K. Tsuchiya,K. Nitta, Switching from allopurinol to febuxostat for the treatment of hyperuricemia and renal function in patients with chronic kidney disease, Clin Rheumatol. 33 (2014) 1643-1648. doi: 10.1007/s10067-014-2745-5 [88]H. W. Chou, H. T. Chiu, C. W. Tsai, I. W. Ting, H. C. Yeh, H. C. Huang, C. C.

ACCEPTED MANUSCRIPT Kuo,C. K. R. Group, Comparative effectiveness of allopurinol, febuxostat and benzbromarone on renal function in chronic kidney disease patients with hyperuricemia: a 13-year inception cohort study, Nephrol. Dial. Transplant. (2017).

RI PT

doi: 10.1093/ndt/gfx313 [89]S. Kim, H. J. Kim, H. S. Ahn, S. W. Oh, K. H. Han, T. H. Um, C. R. Cho,S. Y. Han, Renoprotective effects of febuxostat compared with allopurinol in patients with

M AN U

(2017) 274-281. doi: 10.23876/j.krcp.2017.36.3.274

SC

hyperuricemia: A systematic review and meta-analysis, Kidney Res. Clin. Pract. 36

[90]A. Sezai, M. Soma, K. Nakata, S. Osaka, Y. Ishii, H. Yaoita, H. Hata,M. Shiono, Comparison of febuxostat and allopurinol for hyperuricemia in cardiac surgery patients with chronic kidney disease (NU-FLASH trial for CKD), J Cardiol. 66 (2015)

TE D

298-303. doi: 10.1016/j.jjcc.2014.12.017

[91]J. A. Singh,J. D. Cleveland, Comparative effectiveness of allopurinol versus febuxostat for preventing incident renal disease in older adults: an analysis of claims

data,

Ann

EP

Medicare

Rheum

Dis.

76

(2017)

1669-1678.

doi:

AC C

10.1136/annrheumdis-2017-211210 [92]T. Hosoya, Y. Ogawa, H. Hashimoto, T. Ohashi,R. Sakamoto, Comparison of topiroxostat and allopurinol in Japanese hyperuricemic patients with or without gout: a phase 3, multicentre, randomized, double-blind, double-dummy, active-controlled, parallel-group study, J. Clin. Pharm. Ther. 41 (2016) 290-297. doi: 10.1111/jcpt.12391 [93]T. Nakamura, T. Murase, M. Nampei, N. Morimoto, N. Ashizawa, T. Iwanaga,R. Sakamoto, Effects of topiroxostat and febuxostat on urinary albumin excretion and

ACCEPTED MANUSCRIPT plasma xanthine oxidoreductase activity in db/db mice, Eur. J. Pharmacol. 780 (2016) 224-231. doi: 10.1016/j.ejphar.2016.03.055 [94]A. Sezai, K. Obata, K. Abe, S. Kanno,H. Sekino, Cross-Over Trial of Febuxostat

Circ. J. 81 (2017) 1707-1712. doi: 10.1253/circj.CJ-17-0438

RI PT

and Topiroxostat for Hyperuricemia With Cardiovascular Disease (TROFEO Trial),

[95]F. Perez-Ruiz, J. S. Sundy, J. N. Miner, M. Cravets,C. Storgard, Lesinurad in

SC

combination with allopurinol: results of a phase 2, randomised, double-blind study in

M AN U

patients with gout with an inadequate response to allopurinol, Ann. Rheum. Dis. 75 (2016) 1074-1080. doi: 10.1136/annrheumdis-2015-207919

[96]K. G. Saag, D. Fitz-Patrick, J. Kopicko, M. Fung, N. Bhakta, S. Adler, C. Storgard, S. Baumgartner,M. A. Becker, Lesinurad Combined With Allopurinol: A

TE D

Randomized, Double-Blind, Placebo-Controlled Study in Gout Patients With an Inadequate Response to Standard-of-Care Allopurinol (a US-Based Study), Arthritis Rheumatol. 69 (2017) 203-212. doi: 10.1002/art.39840

EP

[97]T. Bardin, R. T. Keenan, P. P. Khanna, J. Kopicko, M. Fung, N. Bhakta, S. Adler,

AC C

C. Storgard, S. Baumgartner,A. So, Lesinurad in combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study), Ann. Rheum. Dis. 76 (2017) 811-820. doi: 10.1136/annrheumdis-2016-209213 [98]S. L. Stocker, G. G. Graham, A. J. McLachlan, K. M. Williams,R. O. Day, Pharmacokinetic and pharmacodynamic interaction between allopurinol and probenecid in patients with gout, J Rheumatol 38 (2011) 904-910. doi:

ACCEPTED MANUSCRIPT 10.3899/jrheum.101160 [99]S. C. Kim, T. Neogi, E. H. Kang, J. Liu, R. J. Desai, M. Zhang,D. H. Solomon, Cardiovascular Risks of Probenecid Versus Allopurinol in Older Patients With Gout, J.

RI PT

Am. Coll. Cardiol. 71 (2018) 994-1004. doi: 10.1016/j.jacc.2017.12.052 [100]R. Case, B. Wentworth,G. Jester, Effective uric acid reduction with probenecid and febuxostat in a patient with chronic kidney disease, BMJ Case Rep. 2018 (2018).

SC

doi: 10.1136/bcr-2017-222845

M AN U

[101]S. Yoon, D. Shin, H. Lee, I. J. Jang,K. S. Yu, Pharmacokinetics, pharmacodynamics, and tolerability of LC350189, a novel xanthine oxidase inhibitor, in healthy subjects, Drug Des. Devel. Ther. 9 (2015) 5033-5049. doi: 10.2147/dddt.S86884

TE D

[102]L. K. Stamp, T. R. Merriman,J. A. Singh, Expert opinion on emerging urate-lowering therapies, Expert. Opin. Emerg. Drugs. 23 (2018) 201-209. doi: 10.1080/14728214.2018.1527899

EP

[103]J. S. Sundy, N. J. Ganson, S. J. Kelly, E. L. Scarlett, C. D. Rehrig, W. Huang,M.

AC C

S. Hershfield, Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant mammalian urate oxidase in patients with refractory gout, Arthritis Rheum. 56 (2007) 1021-1028. doi: 10.1002/art.22403 [104]E. Sands, A. Kivitz, L. Johnston,T. K. Kishimoto, THU0422 SEL-212: enhanced serum uric acid control in hyperuricemic patients through selective mitigation of anti-drug antibodies against pegsiticase, Ann. Rheum. Dis. 76 (2017) 367. doi: 10.1136/annrheumdis-2017-eular.3548

ACCEPTED MANUSCRIPT [105]G. B. Evans, R. H. Furneaux, A. Lewandowicz, V. L. Schramm,P. C. Tyler, Synthesis of Second-Generation Transition State Analogues of Human Purine Nucleoside

Phosphorylase,

J

Med.

Chem.

46

(2003)

5271-5276.

doi:

RI PT

10.1021/jm030305z [106]Y. Shi,G. Williamson, Quercetin lowers plasma uric acid in pre-hyperuricaemic males: a randomised, double-blinded, placebo-controlled, cross-over trial, Br. J. Nutr.

SC

115 (2016) 800-806. doi: 10.1017/s0007114515005310

M AN U

[107]J. Huang, S. Wang, M. Zhu, J. Chen,X. Zhu, Effects of genistein, apigenin, quercetin, rutin and astilbin on serum uric acid levels and xanthine oxidase activities in normal and hyperuricemic mice, Food Chem. Toxicol. 49 (2011) 1943-1947. doi: 10.1016/j.fct.2011.04.029

attenuates

TE D

[108]L. Chen, Z. Lan, Y. Zhou, F. Li, X. Zhang, C. Zhang, Z. Yang,P. Li, Astilbin hyperuricemia

hyperuricemic

rats,

and

Planta.

ameliorates Medica.

nephropathy 77

(2011)

in

fructose-induced

1769-1773.

doi:

EP

10.1055/s-0030-1271135

AC C

[109]M. Wang, J. Zhao, N. Zhang,J. Chen, Astilbin improves potassium oxonate-induced hyperuricemia and kidney injury through regulating oxidative stress and inflammation response in mice, Biomed Pharmacother. 83 (2016) 975-988. doi: 10.1016/j.biopha.2016.07.025 [110]X. Meng, Z. Mao, X. Li, D. Zhong, M. Li, Y. Jia, J. Wei, B. Yang,H. Zhou, Baicalein decreases uric acid and prevents hyperuricemic nephropathy in mice, Oncotarget. 8 (2017) 40305-40317. doi: 10.18632/oncotarget.16928

ACCEPTED MANUSCRIPT [111]Y. Wang, G. Zhang, J. Pan,D. Gong, Novel insights into the inhibitory mechanism of kaempferol on xanthine oxidase, J. Agric. Food Chem. 63 (2015) 526-534. doi: 10.1021/jf505584m

RI PT

[112]J. Yan, G. Zhang, Y. Hu,Y. Ma, Effect of luteolin on xanthine oxidase: inhibition kinetics and interaction mechanism merging with docking simulation, Food Chem. 141 (2013) 3766-3773. doi: 10.1016/j.foodchem.2013.06.092

SC

[113]Y. Lin, P. G. Liu, W. Q. Liang, Y. J. Hu, P. Xu, J. Zhou, J. B. Pu,H. J. Zhang,

M AN U

Luteolin-4'-O-glucoside and its aglycone, two major flavones of Gnaphalium affine D. Don, resist hyperuricemia and acute gouty arthritis activity in animal models, Phytomedicine. 41 (2018) 54-61. doi: 10.1016/j.phymed.2018.02.002 [114]L. Hongyan, W. Suling, Z. Weina, Z. Yajie,R. Jie, Antihyperuricemic effect of in

potassium

oxonate-induced

hyperuricemic

rats,

Biomed.

TE D

liquiritigenin

Pharmacother. 84 (2016) 1930-1936. doi: 10.1016/j.biopha.2016.11.009 [115]C. P. Wang, X. Wang, X. Zhang, Y. W. Shi, L. Liu,L. D. Kong, Morin improves

EP

urate excretion and kidney function through regulation of renal organic ion

AC C

transporters in hyperuricemic mice, J. Pharm. Pharm. Sci. 13 (2010) 411-427. doi: 10.18433/j3q30h [116]Z.

Yu,

W.

P.

Fong,C.

H.

Cheng,

The

dual

actions

of

morin

(3,5,7,2',4'-pentahydroxyflavone) as a hypouricemic agent: uricosuric effect and xanthine oxidase inhibitory activity, J Pharmacol. Exp. Ther. 316 (2006) 169-175. doi: 10.1124/jpet.105.092684 [117]Z. Yu, W. P. Fong,C. H. Cheng, Morin (3,5,7,2',4'-pentahydroxyflavone) exhibits

ACCEPTED MANUSCRIPT potent inhibitory actions on urate transport by the human urate anion transporter (hURAT1) expressed in human embryonic kidney cells, Drug Metab. Dispos. 35 (2007) 981-986. doi: 10.1124/dmd.106.012187

RI PT

[118]Q. H. Hu, C. Wang, J. M. Li, D. M. Zhang,L. D. Kong, Allopurinol, rutin, and quercetin attenuate hyperuricemia and renal dysfunction in rats induced by fructose intake: renal organic ion transporter involvement, Am J Physiol Renal Physiol. 297

SC

(2009) F1080-1091. doi: 10.1152/ajprenal.90767.2008

M AN U

[119]Q. H. Hu, X. Zhang, Y. Pan, Y. C. Li,L. D. Kong, Allopurinol, quercetin and rutin ameliorate renal NLRP3 inflammasome activation and lipid accumulation in fructose-fed

rats,

Biochem

10.1016/j.bcp.2012.03.005

Pharmacol.

84

(2012)

113-125.

doi:

TE D

[120]Q. H. Hu, X. Zhang, X. Wang, R. Q. Jiao,L. D. Kong, Quercetin regulates organic ion transporter and uromodulin expression and improves renal function in hyperuricemic mice, Eur J Nutr. 51 (2012) 593-606. doi: 10.1007/s00394-011-0243-y

EP

[121]F. Yao, R. Zhang, R. Fu,W. He, Preventive and therapeutic effects of quercetin

AC C

on hyperuricemia and renal injury in rats, Wei sheng yan jiu = Journal of hygiene research 40 (2011) 175-177. doi: [122]J. X. Zhu, Y. Wang, L. D. Kong, C. Yang,X. Zhang, Effects of Biota orientalis extract and its flavonoid constituents, quercetin and rutin on serum uric acid levels in oxonate-induced mice and xanthine dehydrogenase and xanthine oxidase activities in mouse liver, J Ethnopharmacol. 93 (2004) 133-140. doi: 10.1016/j.jep.2004.03.037 [123]C. Zhang, R. Wang, G. Zhang,D. Gong, Mechanistic insights into the inhibition

ACCEPTED MANUSCRIPT of quercetin on xanthine oxidase, Int. J. Biol. Macromol. 112 (2018) 405-412. doi: 10.1016/j.ijbiomac.2018.01.190 [124]Y. S. Chen, Q. H. Hu, X. Zhang, Q. Zhu,L. D. Kong, Beneficial effect of rutin

(2013) 75-83. doi: 10.1159/000351703

RI PT

on oxonate-induced hyperuricemia and renal dysfunction in mice, Pharmacology. 92

[125]J. Pan, M. Shi, L. Li, J. Liu, F. Guo, Y. Feng, L. Ma,P. Fu, Pterostilbene, a

SC

bioactive component of blueberries, alleviates renal fibrosis in a severe mouse model

10.1016/j.biopha.2018.11.022

M AN U

of hyperuricemic nephropathy, Biomed. Pharmacother. 109 (2019) 1802-1808. doi:

[126]T. Hayashi, K. Sawa, M. Kawasaki, M. Arisawa, M. Shimizu,N. Morita, Inhibition of Cow's Milk Xanthine Oxidase by Flavonoids, J. Nat. Prod. 51 (1988)

TE D

345-348. doi: 10.1021/np50056a030

[127]S. F. Mo, F. Zhou, Y. Z. Lv, Q. H. Hu, D. M. Zhang,L. D. Kong, Hypouricemic action of selected flavonoids in mice: structure-activity relationships, Biol. Pharm.

EP

Bull. 30 (2007) 1551-1556. doi:

AC C

[128]F. Haidari, S. A. Keshavarz, M. Mohammad Shahi, S. A. Mahboob,M. R. Rashidi, Effects of Parsley (Petroselinum crispum) and its Flavonol Constituents, Kaempferol and Quercetin, on Serum Uric Acid Levels, Biomarkers of Oxidative Stress

and

Liver

Xanthine

Oxidoreductase

Aactivity

Hyperuricemic Rats, Iran J Pharm Res. 10 (2011) 811-819. doi:

in

Oxonate-Induced

ACCEPTED MANUSCRIPT

URAT1i

Plasma protein binding rate

t1/2

Excretion

Utilization in CKD

Allopurinol

Ki: 700 nM

1h

Negligible

0.7-1.5 h

Kidney

Adjust to GFR

Febuxostat

XO Ki: 0.6 nM XDH Ki: 3.1 nM

1h

99%

10.8 h

Kidney, gut

No adjustment

Topiroxostat

Ki: 5.7 nM

1-2 h

98%

6h

Kidney, gut

No adjustment

Probenecid

OAT1 IC50:12.1 µM OAT3 IC50: 9.0 µM OAT4 IC50: 54.9 µM

1-5 h

83-95%

4-12 h

Kidney

Prohibited if GFR < 50ml/min

2-3 h

99%

13 h

Gut

/

1-4 h

98%

5h

Kidney, gut

As an add-on therapy

Benzbromarone

Lesinurad

TE D

M AN U

SC

tmax

Chemical structure

EP

XORi

Inhibition

Agents

URAT1 IC50: 0.22 µM

AC C

Target

RI PT

Table 1. Pharmacological characteristics of commercial urate-lowering agents.

URAT1 IC50: 7.3 µM OAT4 IC50: 3.7 µM

ACCEPTED MANUSCRIPT

Pegloticase

PEGylated recombinant mammalian uricase

IC50: 0.104 µg/mL for UA

/

/

6.4-13.8 d

RI PT

Uricase

/

No adjustment

AC C

EP

TE D

M AN U

SC

tmax: the time it takes the drug to reach the maximum concentration, t1/2: the time it takes half of the drug to be removed by biological processes, CKD: Chronic kidney disease, XORi: inhibitor of xanthine oxidoreductase, XO: xanthine oxidase, XDH: xanthine dehydrogenase, URAT1i: inhibitor of URAT1, GFR: glomerular filtration rate, UA: uric acid.

ACCEPTED MANUSCRIPT

Mechanism

Inhibition

Current status

LC350189

XORi

SC

Phase I LG Chem Ltd.

Merbarone (RLBN1001)

XORi URAT1i

Verinurad (RDEA3170)

/

M AN U

TE D URAT1i

EP

Arhalofenate (MBX-102,)

Chemical structure

AC C

Compound

RI PT

Table 2. Current status of pipeline urate-lowering agents.

URAT1i

XORi IC50: 274µM URAT1 IC50: 5.4µM

EC50: 12µM

IC50: 23nM

Phase I

Phase II CymaBay Therapeutics Inc.

Phase II AstraZeneca plc

ACCEPTED MANUSCRIPT

/

/

UR1102

Inhibits URAT1 and to a lesser extent OAT1 and OAT3

URAT1 Ki: 57nM OAT1 Ki: 7.2µM OAT3 Ki: 2.4µM

/

Dotinurad

Uricosuric

IC50: 3.6 µM for UA

Phase III Fuji Yakuhin Co. Ltd.

URAT1i

/

Phase II Jiangsu HengRui Medicine Co., Ltd.

PNPi

Ki: 1.1nM

Phase II BioCryst Pharmaceuticals Inc.

Ulodesine (R3421, BCX4208)

SC

M AN U

TE D EP

/

AC C

SHR4640

RI PT

Levotofisopam (S-tofisopam)

Phase II Pharmos Corp.

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

XORi: inhibitor of xanthine oxidoreductase, URAT1i: inhibitor of URAT1, PNPi: inhibitor of purine nucleic phosphorylase, UA: uric acid.

ACCEPTED MANUSCRIPT

Abundantly present in common fruits and vegetables

No

Smilax china L.

No

Scutellariae radix

AC C

Baicalein

EP

TE D

Astilbin

Source

Yes IC50=3.3 µM

Renoprotection

SC

Apigenin

Chemical structure

Interaction with urate transporters

/

Reference

SCr↓, BUN↑

[108]

GLUT9, URAT1, ABCG2, OAT1/3

SCr↓, BUN↓ Against TGF-β1, CTGF, PGE2, IL-1, MSU Against Thioredoxin-interacting protein expression and its related inflammation

[108-110]

/

SCr↓, BUN↓, Urine microalbumin↓ Suppresses hyperuricemia-induced renal fibrosis through matrix metalloproteinases; Inhibits hyperuricemia-induced epithelial-mesenchymal transition process. Ameliorated XOR-dependent and NADPH oxidase-dependent oxidative stress

[111, 127]

M AN U

Agents

XOR inhibitor

RI PT

Table 3. Characteristics of natural products in hyperuricemia-induced nephropathy.

ACCEPTED MANUSCRIPT

No

Kaempferol

Widely exist in daily vegetables and fruits

Yes Ki=6.77µM

Luteolin

Gnaphalium D. Don

affine

Yes Ki=2.38µM

Luteolin-4’-O -glucoside

Gnaphalium D. Don

affine

Liquiritigenin

Glycyrrhizae Radix et Rhizoma

SCr↓, BUN↓

[108]

/

[112]

GLUT9, URAT1,

IL-1β↓, TNF-α↓

[113,114]

Yes

GLUT9, URAT1,

IL-1β↓, TNF-α↓

[114]

Yes IC50=11.3 µM

/

TE D

M AN U

/

EP

AC C

/

RI PT

Genista tincoria

SC

Genistein

Suppressing renal AQP4/NF-κB/IκBα NLRP3 inflammasome activation

and

[115, 127]

ACCEPTED MANUSCRIPT

Allium cepa L.

Yes Ki=7.9µM

Yes Ki=0.472µM

[112, 116-118]

GLUT9, URAT1, OAT1

SCr↓, BUN↓ PEG2↑, NO ↑ Improvement in oxidative stress, SOD↑ Ameliorate NLRP3 inflammasome activation

[119-124]

GLUT9, URAT1, OAT1

SCr↓, BUN↓ PEG2↑, NO↑ Ameliorate NLRP3 inflammasome activation

[108, 120, 125]

SCr↓, BUN↓ Urine albumin↓, urine ACR↓ Anti-fibrosis via suppression of the activation of TGF-β/Smad3, Src, STAT3 signaling pathway

[126]

RI PT SCr↓

M AN U

Quercetin

Morus alba L.

SC

Morin

URAT1 (Ki=5.74µM) GLUT9 OAT1

Carpobrotus edulis

Pterostilbene

Found in almonds, Vaccinium berries, grape leaves and vines, blueberries

Yes

AC C

EP

TE D

Rutin

/

/

SCr: serum creatinine, BUN: blood urea nitrogen, ACR: albumin-to-creatinine ratio

119, 123,

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT Highlights Illustrating urate-lowering importance in hyperuricemia with CKD; Pharmacological characteristics of urate-lowering agents and pipeline agents;

RI PT

Medicinal chemist and nephrologist focused on appropriate urate-lowering agents

AC C

EP

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M AN U

SC

for CKD;