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Crystalline Arthritis
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Hyperuricemia is primarily due to inadequate uric acid excretion in the kidneys. Several well-studied urate transporters, predominantly in the kidney (but also the gut), are responsible for uric acid handling. Genome-wide association studies (GWAS) identified SLC2A9 (encoding GLUT9), SLC22A12 (encoding URAT1), SLC17A1 (encoding NPT1), and ABCG2 as key genes. A heritability analysis of a large twin cohort reported the concordance of hyperuricemia to be 53% in monozygotic twins and 24% in dizygotic twins.5
Clinical Pharmacology of the Anti-Tuberculosis Drugs
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Gerry Davies, Charles Peloquin
In early studies of PZA monotherapy with doses of 50 mg/kg or greater, hepatotoxicity occurred in approximately 6% of patients and available data suggest similar rates at lower doses during combination therapy.66 However, 2RZ regimens for LTBI with PZA given intermittently at doses of up to 50 mg/kg were associated with discontinuation rates due to drug-induced liver injury of more than 8%, leading to the removal of the regimen from guidelines.67 Though it can be difficult to judge which individual drug is culpable in combination regimens, current guidelines do not recommend reintroducing PZA after a severe episode of DILI. POA is a high-affinity substrate of the renal organic anion transporter URAT1 (SLC22A12) which stimulates reabsorption of uric acid from the proximal tubule.68 Increased plasma uric acid concentrations may be associated with arthralgia and pruritis which appears to be dose-related66 but very rarely results in clinical gout. PZA may also be associated with significant gastrointestinal intolerance.
Inosine induces acute hyperuricaemia in rhesus monkey (Macaca mulatta) as a potential disease animal model
Published in Pharmaceutical Biology, 2021
Dong-hong Tang, Chen-yun Wang, Xi Huang, Hong-kun Yi, Zhe-li Li, Kai-li Ma, You-song Ye, Jian-wen Zhang
Uric acid is excreted and reabsorbed from the kidneys and gut via uric acid transporters, whose aberrant expression is linked to HUA. Urate transporter 1 (URAT1, encoded by SLC22A12) is an important organic anion transporter that maintains uric acid homeostasis. It is located in the brush border of proximal tubular epithelial cells and mainly mediates the reabsorption of uric acid. Intracellular urate is released through glucose transporter 9 (GLUT9, encoded by SLC2A9). A multiple specific anion transporter, organic anion transporter 4 (encoded by SLC22A11), is located in the apical membrane of epithelial cells and has been demonstrated to promote urate reabsorption (Wright et al. 2010; Xu et al. 2017). ABCG2, a half-transporter protein with an ATP-binding cassette, has also been genetically linked to serum uric acid (SUA) level, HUA and gout (Wright et al. 2010; Xu et al. 2017). ABCG2 mediates renal and/or extra-renal urate excretion as a high-capacity exporter and is abundantly expressed in the proximal tubule cells, at the apical membrane, and in hepatocytes (Woodward et al. 2009; Hosomi et al. 2012).
Antihyperuricemic efficacy of Scopoletin-loaded Soluplus micelles in yeast extract/potassium oxonate-induced hyperuricemic mice
Published in Drug Development and Industrial Pharmacy, 2020
Yingchun Zeng, Yu Ma, Zhengyu Yang, Jiamin Mao, Yaxin Zheng
In the body, urate exists as an organic anion and needs membrane transporters to permeate into the cell across the plasma membrane [28]. Some of the renal organic anion transporters play key roles in this process, such as URAT1 [29] (encoded by SLC22A12), GLUT9 [30] (encoded by SLC2A9), and OAT1 [31] (encoded by SLC22A6). URAT1, an anion exchanger, could transport urate in exchange for organic anions such as Cl−, lactate, and pyrazinoic acid [32]. It is a key determinant in urate reabsorption and a therapeutic target of some uricosuric agents [33]. GLUT9 has been identified as a urate transporter. It was strongly associated with the regulation of urine urate level in a voltage-dependent manner [34]. In addition, OAT1 was identified as a molecular transporter involving in the secretion of uric acid in the first step [35]. In the present study, Sco attenuated the dysregulation of renal URAT1, GLUT9, and OAT1 (Figure 7), which explained the reason why the urine urate level of Sco-treated mice was increased. With enhanced Sco concentration in kidney, Sco-Ms restored the alteration of renal URAT1, GLUT9, and OAT1 expressions in hyperuricemic mice more effectively, thus exhibiting superior uricosuric effect than Sco. Generally, approximately 80–90% of the gout patients were ascribed to a reduction of urate excretion [36]. Therefore, these three renal urate transporters were important targets for Sco to treat gout.
ABCG2 as a therapeutic target candidate for gout
Published in Expert Opinion on Therapeutic Targets, 2018
Kyoko Fujita, Kimiyoshi Ichida
The regulatory mechanism behind uric acid overproduction has not been identified, with the exception of certain urate metabolism disorders involving hypoxanthine-guanine phosphoribosyltransferase deficiency, increased purine nucleotide degradation, and accelerated ATP breakdown. On the other side of serum uric acid homeostasis, the kidney is known to be the main urate excretion route, and its role as such has been well-studied. Uric acid which is not protein bound is filtered at the glomerulus, before being reabsorbed and secreted at the renal tubules, with 6 to 10% of uric acid from glomerular filtration ultimately being excreted in urine. A number of proximal renal tubule urate transporters have been identified (Figure 1). Of these, urate transporter 1 (URAT1/SLC22A12) and glucose transporter 9 (GLUT9/SLC2A9) on the luminal (apical) and basolateral membranes, respectively, play key roles in uric acid reabsorption, while ATP-binding cassette, sub-family G, member 2 (ABCG2) on the luminal membrane is important in its secretion. In addition, there exist other proteins indirectly associated with uric acid transport, e.g. sodium-dependent monocarboxylate transporter 1/2 (SMCT1/SLC5A8, SMCT2/SLC5A12) and PDZ domain-containing 1 (PDZK1) [3,10]. There is strong evidence to suggest that differences between individuals in serum uric acid level may be explained by urate transporter variants [3,11].