Increasing Excretion of Urate With Displacing Agents in Man*

Whitehouse, M. W.; Kippen, Ian; Klinenberg, James R.; Schlosstein, Lee; Campion, David S.; Bluestone, Rodney

doi:10.1111/j.1749-6632.1973.tb20492.x

Cited by 14 publications

(2 citation statements)

References 11 publications

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“…T h e authors have previously proposed that the in vitro displacement of urate from its albumin binding site by an acidic anion was highly indicative of potential uricosuric activity by that anion when administered to humans (1). T h e original experiments on which this hypothesis was based utilized an equilibrium dialysis method to measure urate binding and a fluorescence-quenching technique to detect displacement of 5-dimethylamino-naphthalene-1-sulfonamide (DNSA) from binding sites on human serum albumin T h e recent development of a continuous ultrafiltration technique for measuring urate binding under more physiologic conditions has permitted a reexamination of urate displacement from serum albumin in vitro by certain drugs (3).…”

Section: Rodney Bluestone David Campion and James R Klinenbergmentioning

confidence: 99%

Halofenate

Bluestone

Campion

Klinenberg

1975

Arthritis & Rheumatism

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T h e authors have previously proposed that the in vitro displacement of urate from its albumin binding site by an acidic anion was highly indicative of potential uricosuric activity by that anion when administered to humans (1). T h e original experiments on which this hypothesis was based utilized an equilibrium dialysis method to measure urate binding and a fluorescence-quenching technique to detect displacement of 5-dimethylamino-naphthalene-1-sulfonamide (DNSA) from binding sites on human serum albumin T h e recent development of a continuous ultrafiltration technique for measuring urate binding under more physiologic conditions has permitted a reexamination of urate displacement from serum albumin in vitro by certain drugs (3). T h e displacement of sodium (2). urate by uricosuric agents from binding sites on human serum albumin (HSA) and normal serum was thereby demonstrated under in vitro physiologic conditions (pH 7.4, ionic strength 0.16). At 37OC, 0.5 mM sodium salicylate reduced urate bound to 5 g per 100 ml HSA from 19.6% to 9.7%. At room temperature (22.5OC) 22.6y0 urate was bound to 5 g per 100 ml HSA; this was reduced to 12.3y0 by 0.5 mM salicylate, to 9.2y0 by 0.5 mM phenylbutazone, to 14.67, by 0.2 mM diflumidone, and to 17.9a/, by 0.2 mM sulfaethyladiazole (Figure 1). At 22.5"C pooled normal human serum containing 4.8 g per 100 ml albumin bound 23.5% urate, and comparable displacement by drugs was demonstrated (4).During the screening of numerous novel compounds for in vitro urate displacing properties, four drugs or their metabolites were identified as potentially useful new uricosurics (5). In short-term clinical trials these four agents (sulfaethylthiadiazole, diflumidone sodium, W-2354, and halofenate) were all clearly uricosuric, lowering serum urate concentrations and significantly increasing the renal clearance of urate (6).Halofenate was particularly interesting. It is now widely recognized that many patients with gout have Type IV hyperlipoproteinemia characterized predominantly by elevated serum triglyceride concentrations (7). Moreover this association is only partly explained by concomitant obesity or heavy alcohol

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Section: Rodney Bluestone David Campion and James R Klinenbergmentioning

confidence: 99%

Halofenate

Bluestone

Campion

Klinenberg

1975

Arthritis & Rheumatism

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“…A clear documentation of altered binding in clinically known disturbances of purine metabolism or its changes following drug administration [8][9][10] could help to understand mechanisms of renal u.a. transport in humans which are not yet fully understood, e.g.…”

Section: Introductionmentioning

confidence: 99%

Ultrafiltrable Uric Acid in Serum of Healthy Humans and Patients with Renal Calcium Lithiasis

Schwille¹,

Bornhof²

1976

Nephron

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Ultrafiltrable serum uric acid (u. a.) was determined by ultrafiltration under in vivo conditions in humans using a reliable technique described in detail. It could be demonstrated that u.a. binding to macromolecules occurs in healthy humans (controls) and in patients with renal calcium stones. The percentage of free u. a. in controls (n = 60) averages 86.2 ± 0.9 SEM. With increasing age, bound u.a. rises slightly. On the other hand, younger ( < 40 years) stone patients have significantly more bound u. a. than matched controls (80.7 ± 1.0 SEM; p < 0.001), whereas this is not found in elderly patients. The degree of binding is not related to concentration of plasma proteins but inversely related to free fatty acid concentration in healthy controls (r = ^–0.52; p < 0.01). It is suggested that no augmentation of tubular u. a. filtered by the glomeruli could have occurred. The origin of fasting hyperuricosuria shown earlier to be a prominent feature of young renal calcium stone formers is yet unknown.

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Pharmacokinetics and Temperature

Ballard

1974

Journal of Pharmaceutical Sciences

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Increasing Excretion of Urate With Displacing Agents in Man*

Cited by 14 publications

References 11 publications

Halofenate

Halofenate

Ultrafiltrable Uric Acid in Serum of Healthy Humans and Patients with Renal Calcium Lithiasis

Pharmacokinetics and Temperature

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