Recent developments in our understanding of the renal basis of hyperuricemia and the development of novel antihyperuricemic therapeutics

Abstract

Although dietary, genetic, or disease-related excesses in urate production may contribute to hyperuricemia, impaired renal excretion of uric acid is the dominant cause of hyperuricemia in the majority of patients with gout. The aims of this review are to highlight exciting and clinically pertinent advances in our understanding of how uric acid is reabsorbed by the kidney under the regulation of urate transporter (URAT)1 and other recently identified urate transporters; to discuss urate-lowering agents in clinical development; and to summarize the limitations of currently available antihyperuricemic drugs. The use of uricosuric drugs to treat hyperuricemia in patients with gout is limited by prior urolothiasis or renal dysfunction. For this reason, our discussion focuses on the development of the novel xanthine oxidase inhibitor febuxostat and modified recombinant uricase preparations.

Figure 1

Urate anion transport function of URAT1 in renal proximal tubule epithelial cells. Schematic representation of urate reabsorption in the proximal tubule. Urate reabsorption at the apical (luminal) membrane is critically regulated by URAT1. The organic anion transporter URAT1 exchanges tubular lumen urate with anions inside proximal tubular epithelial cells. Potent stimulators of the exchange process include the intracellular organic ions lactate, nicotinate, and the monocarboxylate metabolite of the anti-tuberculous drug pyrazinimde. Certain intracellular inorganic ions, including chloride, also stimulate urate exchange by URAT1 but with lesser potency. As depicted, urate reabsorption is suppressed at the luminal membrane by some drugs, including benzbromarone, probenecid, losartan, and sulfinpyrazone, consistent with their urisouric properties. Other agents. that affect urate reabsorption in the proximal tubule, including furosemide and salicylates, may act partly by regulating URAT1 function.

Figure 2

Xanthine oxidase in the context of purine metabolism. Schematic representation of human purine metabolic pathways, culminating in the production of uric acid. Purine nucleotides are synthesized by alternative pathways, each requiring the key regulatory intermediate 5-phosphoribosyl 1-pyrophosphate (PRPP), which is synthesized from ATP and ribose-5-P in a reaction catalyzed by PRPP synthetase. The pathway of purine synthesis de novo involves a sequence of 10 reactions by means of which a purine ring is synthesized on a ribose-phosphate backbone donated by PRPP. The first reaction in the pathway is the rate-limiting step and is catalyzed by the enzyme amidophopshoribosyltransferase (AmidoPRT). The subsequent 9 reactions in the de novo pathway are represented by the dashed arrow. The alternative pathways of purine nucleotide synthesis are single step processes by which preformed purine bases (adenine, Ade; hypoxanthine (Hyp); guanine, Gua) are salvaged in reactions catalyzed by the phosphoribosyltransferase (PRT) enzymes adeninePRT (APRT) and hypoxanthine-guanine (HPRT), respectively. Regulation of nucleotide synthesis is effected mainly at the AmidoPRT step, by means of antagonistic allosteric regulation of the activity of AmidoPRT by inhibitory (-) purine nucleotide products and PRPP activation. Purine nucleotide products also inhibit PRPP synthetase activity. Purine nucleotides and nucleosides are readily interconverted by means of an extensive and complex series of enzyme-catalyzed reactions that provide the cellular requirements for balanced availability of adenine and guanine nucleotides and nucleosides. Phosphorolysis of the nucleosides inosine and guanosine result in production of Hyp and Gua, which are either salvaged (in the HPRT reaction) or are ultimately and irreversibly oxidized through the base xanthine (Xan) to the end product, uric acid, in reactions catalyzed by xanthine oxidase.

Figure 3

Reactions catalyzed by xanthine oxidase (also known as xanthine oxidoreductase). The enzyme exists in dehydrogenase and oxidase forms, accepting NAD⁺ in the former conformation and O₂ in the latter. Reversible interconversion of the forms involves disulfide bond formation and disruption.

Figure 4

Comparison of structures of allopurinol, oxypurinol, and febuxostat. Clinically utilized xanthine oxidase inhibitors. Allopurinol and its oxidation product oxypurinol are hydroxypyrazolopyrimidine analogues, respectively, of hypoxanthine and xanthine. As such, each can affect the activities of enzymes of purine and pyrimidine metabolism other than xanthine oxidase. Febuxostat is a thiazolecarboxylic acid derivative that does not resemble a purine or pyrimidine and has shown substantial specificity as a xanthine oxidase inhibitor [50].

Figure 5

Comparative effects of allopurinol and benzbromarone on plasma urate levels. Initial and final plasma urate (Pur) after standard doses of urate-lowering drugs allopurinol (300 mg/day) or benzbromarone (100 mg/day). *For final versus initial plasma urate, P < 0.01 for allopurinol groups and P < 0.001 for benzbromarone group. Adapted from [39]. Copyright 1998 with permission from BMJ Publishing Group.

Figure 6

Febuxostat blockade of substrate access to the active site of both reduced and oxidized xanthine oxidase. Space-taking representation of the interaction of febuxostat and amino acid residues of xanthine oxidase. Febuxostat, represented in green, occupies the channel accessing the Mo-pterin moiety in the active site of xanthine oxidase. In contrast to allopurinol and oxypurinol, which bind directly to the active site and result in competitive inhibition of enzyme activity, febuxostat blocks substrate access to the channel resulting in a pattern of mixed inhibition of enzyme activity. Reprinted with permission from [46]. ^© 2006 American Society for Biochemistry and Molecular Biology.

Figure 7

Multiple sites of allopurinol action on pathways of purine and pyrimidine metabolism. Reactions inhibited by allopurinol are shown in red; reactions unaffected are shown in green. Allopurinol or its metabolites also result in depletion of intracellular 5-phosphoribosyl 1-pyrophosphate (PRPP) concentrations. AMP, adenosine monophosphate; CTP, cytosine triphosphate; GMP, guanosine monophosphate; HGPRT, hypoxanthine-guanine phosphoribosyltransferase; IMP, inosine monophosphate; OMPDC, orotidine-5'-monophosphate decarboxylase; OMP, orotidine monophosphate; OPRT, orotate phosphoribosyltransferase; PNP, purine nucleoside phosphorylase; PRPP, 5-phosphoribosyl 1-pyrophosphate; UMP, uridine monophosphate; UTP, uridine triphosphate; XOD, xanthine oxidase.

Figure 8

Serum urate-lowering efficacy of febuxostat compared with placebo. Subjects with gout and baseline serum urate levels > 8.0 mg/dl received once daily doses of placebo or febuxostat for 28 days. Modified from [52].

Figure 9

Action of uricase to catabolize uric acid to allantoin. Uricase (urate oxidase) gene expression and the depicted uricase reaction are lacking in humans, as discussed in the text. PEGylated recombinant uricase preparations are now under investigation for treatment of refractory hyperuricemia in gout, and have the potential to rapidly reduce ("de-bulk") tophus burden.