Uric acid transporter 1 URAT

Hyperuricemia may be produced by overproduction of uric acid or under-excretion of uric add by the kidneys. Kyperuricemia may progress to acute and chronic gouty arthritis if uric acid (monosodium urate) is deposited in joints and surrounding soft tissue, where it causes inflammation, Uric add is produced from excess endogenous purines as shown in Figure 1-18-5, and is also produced from dietary purines (digestion of nucleic acid in the intestine) by intestinal epithe-lia. Both sources of uric acid are transported in the blood to the kidneys for excretion in urine. 

Roch-Ramel, F., D. de Rougemont, G. Peters, I.M. Weiner Micropuncture study of urate excretion by the kidney of the rat, the Cebus monkey and the rabbit. In S. Silbernagl, F. Lang, R. Greger (eds.). Amino Acid Transport and Uric Acid Transport. Symposium Innsbruck, June 1975. Stuttgart Thieme, 1976b, p. 188-192. 

In 1961 Gutman and Yu proposed a three component system for the regulation of the renal excretion of uric acid in man. The first component of this system is filtration of plasma urate at the glomerulus. While this process is certain to be operative in the human kidney, its quantitative role in the renal excretion of uric acid in man depends upon the extent of urate binding to plasma proteins in vivo. This is a subject that is being discussed in another section of this symposium and will not be considered further in this paper. The second and third component of this system relate to uric acid reabsorption and secretion by the human nephron. Ample data is available to document that both of these processes are operable in the human kidney (Gutman and Yu, 1957 Gutman, et al., 1959), but the relative contribution of each to the final excretion of uric acid has been difficult to determine with conventional clearance techniques. However, a potential solution to this problem of bidirectional uric acid transport appeared in 1967 when Steele and Rieselbach introduced the "pyrazinamide suppression test . 

Most drugs act by reducing active transport rather than by enhancing it. Thus, drugs that promote uric acid loss (uricosuric agents, such as probenecid and sulfinpyrazone) probably inhibit active urate reabsorption, while pyrazinamide, which reduces urate excretion, may block the active tubular secretion of uric acid. A complicating observation is that a drug may primarily inhibit active reabsorption at one dose and active secretion at another, frequently lower, dose. For example, small amounts of salicylate will decrease total urate ex-... 

Renal handling of uric acid. Uric acid may be actively reabsorbed from the ultrafiltrate following its glomerular filtration or it may be secreted from the blood across the basolateral membrane into the proximal tubular cell. Both passive and active transport mechanisms are involved in the handling of urate. Uricosuric drugs at appropriate doses interfere with these processes. 

The uricosuric drugs (or urate diuretics) are anions that are somewhat similar to urate in structure therefore, they can compete with uric acid for transport sites. Small doses of uricosuric agents will actually decrease the total excretion of urate by inhibiting its tubular secretion. The quantitative importance of the secretory... 

When probenecid (ColBENEMID) is given in sufficient amounts, it will block the active reabsorption of uric acid in the proximal tubules following its glomerular filtration, thereby increasing the amount of urate eliminated. In contrast, low dosages of probenecid appear to compete preferentially with plasma uric acid for the proximal tubule anionic transport system and thereby block its access to this active secretory system. The uricosuric action of probenecid, however, is accounted for by the drug s ability to inhibit the active reabsorption of filtered urate. 

Losartan appears to be unique among the ARBs because it inhibits the urate anion transport in renal proximal tubuli hence, it increases uric acid excretion and decreases plasma levels of uric acid in hypertensive patients. This effect is not the consequence of AT] receptor blockade. Since high uric acid levels have been associated with cardiovascular morbidity/mortality, losartan may be the best ARB for patients with gout [7,30,31]. Moreover, losartan was found to decrease ocular pressure in normotensive as well as in hypertensive patients [32]. 

Uricosurics, such as probenecid or benz-bromarone (100 mg/day), promote renal excretion of uric acid. They saturate the organic acid transport system in the proximal renal tubules, making it unavailable for urate reabsorption. When underdosed, they inhibit only the acid secretory system, which has a smaller transport capacity. Urate elimination is then inhibited and a gout attack is possible. In patients with urate stones in the urinary tract, uricosurics are contraindicated. 

A decline in the urinary excretion of uric acid to a level below the rate of production leads to hyperuricemia and an increased miscible pool of sodium urate. Almost all the urate in plasma is freely filtered across the glomerulus. The concentration of uric acid appearing in the urine is determined by multiple renal tubular transport processes in addition to the filtered load. Evidence favors a four-component model including glomerular filtration, tubular reabsorption, tubular secretion, and postsecretory reabsorption. ... 

Factors that decrease uric acid clearance or increase its production will result in an increase in serum urate concentration. Some of these factors are listed in Table 91-1. Drugs that decrease renal clearance of uric acid through modification of filtered load or one of the tubular transport processes are listed in Table 91-2. By enhancing renal urate reabsorption, insulin resistance is also associated with gout. ... 

Another transporter expressed in proximal tubule epithelial cells is URATl. URATl is responsible for the reabsorption of urate in the kidney. Gout, an inflammatory disease, results from elevated body levels of uric acid. It is believed that an inherited deficiency in URATl expression is a causative factor in the disease. Treatment includes administration of uricosuric agents such a probenecid and sulfinpyrazone increase uric acid excretion through inhibition of URATl. 

Uricosuric agents increase the rate of excretion of uric acid. In humans, urate is filtered, secreted, and reabsorbed by the kidneys. Reabsorption predominates, and the amount excreted usually is 10% of that filtered. This process is mediated by a specific transporter, which can be inhibited see Chapter 2). 

Unlike benzbromarone 48, which was not marketed in the United States and had limited availability in Europe due to fatal liver toxicity, lesinurad sodium 49 (RDEA-594), discovered and developed by Ardea Biosciences, is a selective inhibitor of urate-anion transporter (URATl), a transporter in kidney cells that regulates uric acid excretion from the body. Lesinurad is currently in phase III clinical trials as a once-daily treatment for gout. AstraZeneca acquired Ardea Biosciences in April, 2012 due to this advanced drug candidate and two other drug compounds at the cost of 1.26 billion. It was expected that lesinurad would be filing for regulatory approval in the United States and Europe soon. 

Serum uric acid concentration in man is the result of complex biosynthetic, catabolic, and excretory processes. Recent investigations of the urate transport system in the human kidney have provided evidence for a four-component model glomerular filtration, presecretory reabsorption, tubular secretion, and postsecretory reabsorption. ... 

Dietary habits and tubular transport defects of urate explain the excessive uric acid excretion of patients with RCN. An alteration of the renal handling of uric acid may be suspected when hyperuricosuria concurs with hypouricemia normal serum uric acid does not exclude a tubular transport defect of urate. 

Abnormal renal transport of urate may protect some patients with sickle cell cuiemia from hyperuricemia. Meain uric acid excretion was less in hyperuricemic sickle cell anemia patients than in those with a serum uric acid in the normal range (Table 3), Mean urate clearance was 8.3 1.1 ml/min in 8 normouricemic patients compared to 4.0 0.8 ml/min in 8 hyperuricemic patients. Thus, compared to the hyperuricemic patients, the normouricemic... 

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