Studies of uric acid pool size and turnover rate.

Scott, J. T.; Holloway, V P; Glass, H. I.; Arnot, R. N.

doi:10.1136/ard.28.4.366

Cited by 53 publications

(31 citation statements)

References 10 publications

(5 reference statements)

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“…In humans, as mentioned earlier, URAT1 mutations cause severe hypouricemia, and most gout patients are classified as under-excretors (Choi et al, 2005); therefore, URAT1 inhibition would be expected to cause significant urate-lowering in gout patients. On the other hand, Cebus monkeys have a certain level of uricase, and additionally their rate of urate synthesis is 7-8 times that in humans (Scott et al, 1969;Simkin, 1971). Taken together, these facts would suggest that the contribution of URAT1 to urate metabolism is smaller in tufted capuchin monkeys than in humans; that is to say, the effect of UR-1102 or benzbromarone might be slighter in this animal.…”

Section: Novel Urate-lowering Drug Ur-1102 For Cebus Monkeysmentioning

confidence: 67%

Stronger Uricosuric Effects of the Novel Selective URAT1 Inhibitor UR-1102 Lowered Plasma Urate in Tufted Capuchin Monkeys to a Greater Extent than Benzbromarone

Ahn

Ohtomo

Kiyokawa

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Urate-lowering therapy is indispensable for the treatment of gout, but available drugs do not control serum urate levels tightly enough. Although the uricosurics benzbromarone and probenecid inhibit a urate reabsorption transporter known as renal urate transporter 1 (URAT1) and thus lower serum urate levels, they also inhibit other transporters responsible for secretion of urate into urine, which suggests that inhibiting URAT1 selectively would lower serum urate more effectively. We identified a novel potent and selective URAT1 inhibitor, UR-1102, and compared its efficacy with benzbromarone in vitro and in vivo. In human embryonic kidney (HEK)293 cells overexpressing URAT1, organic anion transporter 1 (OAT1), and OAT3, benzbromarone inhibited all transporters similarly, whereas UR-1102 inhibited URAT1 comparably to benzbromarone but inhibited OAT1 and OAT3 quite modestly. UR-1102 at 3-30 mg/kg or benzbromarone at 3-100 mg/kg was administered orally once a day for 3 consecutive days to tufted capuchin monkeys, whose low uricase activity causes a high plasma urate level. When compared with the same dosage of benzbromarone, UR-1102 showed a better pharmacokinetic profile, increased the fractional excretion of urinary uric acid, and reduced plasma uric acid more effectively. Moreover, the maximum efficacy of UR-1102 was twice that of benzbromarone, suggesting that selective inhibition of URAT1 is effective. Additionally UR-1102 showed lower in vitro potential for mechanisms causing the hepatotoxicity induced by benzbromarone. These results indicate that UR-1102 achieves strong uricosuric effects by selectively inhibiting URAT1 over OAT1 and OAT3 in monkeys, and could be a novel therapeutic option for patients with gout or hyperuricemia.

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Section: Novel Urate-lowering Drug Ur-1102 For Cebus Monkeysmentioning

confidence: 67%

Stronger Uricosuric Effects of the Novel Selective URAT1 Inhibitor UR-1102 Lowered Plasma Urate in Tufted Capuchin Monkeys to a Greater Extent than Benzbromarone

Ahn

Ohtomo

Kiyokawa

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…SUA levels are determined by the balance between the production and excretion of uric acid. 10) Xanthine oxidase produces uric acid from hypoxanthine and xanthine. Being responsible for approximately 70% of its elimination, the kidneys play a dominant role in uric acid excretion.…”

mentioning

confidence: 99%

Administered chrysanthemum flower oil attenuates hyperuricemia: mechanism of action as revealed by DNA microarray analysis

Honda

Kawamoto

Tanaka

et al. 2014

Bioscience, Biotechnology, and Biochemistry

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“…Studies in females: Bishop et al 1954;Wyngaarden 1955;Kelley et al 1968. Studies in males: Benedict et al 1949Benedict et al , 1950Geren et al 1950;Bishop et al 1951aBishop et al , b, 1954Buzard et al 1952;Wyngaarden and Stetten 1953;Wyngaarden 1955;Sorensen 1959Sorensen , 1962Eisen and Seegmiller 1961;Seegmiller et al 1961Seegmiller et al , 1968Bowering et al 1969;Scott et al 1969;Dosman et al 1975 Males (~± SD) Females (F-t-range) …”

Section: Resultsmentioning

confidence: 95%

Influence of dietary purines on pool size, turnover, and excretion of uric acid during balance conditions

Löffler¹,

Gröbner²,

Medina

et al. 1982

Res. Exp. Med.

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Pool size, turnover, and excretion of uric acid were investigated in three normal subjects both during purine-free, isoenergetic liquid formula diet and during additional purine administration by use of isotope dilution techniques. The fractional turnover of the uric acid pool was increased during dietary purine administration suggesting an increased total body uric acid clearance as a result of the increase in renal clearance. Fractional turnover increased more in the female subject than in males, while pool size was increased less. It can be calculated from the results obtained that endogenous uric acid synthesis is not inhibited by dietary purines.

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Studies of uric acid pool size and turnover rate.

Cited by 53 publications

References 10 publications

Stronger Uricosuric Effects of the Novel Selective URAT1 Inhibitor UR-1102 Lowered Plasma Urate in Tufted Capuchin Monkeys to a Greater Extent than Benzbromarone

Stronger Uricosuric Effects of the Novel Selective URAT1 Inhibitor UR-1102 Lowered Plasma Urate in Tufted Capuchin Monkeys to a Greater Extent than Benzbromarone

Administered chrysanthemum flower oil attenuates hyperuricemia: mechanism of action as revealed by DNA microarray analysis

Influence of dietary purines on pool size, turnover, and excretion of uric acid during balance conditions

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