The Effect of Dietary Protein on the Clearance of Allopurinol and Oxypurinol

Abstract

A decrease in dietary protein is known to depress renal plasma flow and creatinine clearance. Using a randomized crossover design, we investigated the pharmacokinetics of allopurinol and its principal metabolite, oxypurinol, after oral administration of 600 mg of allopurinol in six normal subjects receiving a high-protein (268 g per day) or low-protein (19 g per day) diet. For allopurinol, the area under the curve of plasma concentration versus time increased by a factor of 1.45 (P less than 0.02), the renal clearance decreased by 28 per cent (P less than 0.02), and the ratio of the clearance of allopurinol to that of creatinine (fractional excretion) was unchanged between the low-protein and high-protein diets. For oxypurinol, the area under the curve increased nearly three-fold (P less than 0.02), the renal clearance decreased by 64 per cent (P less than 0.02), the fractional excretion decreased by 49 per cent (P less than 0.02), and the plasma oxypurinol half-life increased nearly threefold from 17.3 +/- 1.5 (mean +/- S.E.M.) to 49.9 +/- 2.9 hours (P less than 0.02) during the low-protein diet, as compared with the high-protein diet. We conclude that with the low-protein diet, the absorption, metabolism, and excretion of allopurinol were minimally altered but the total-body clearance of oxypurinol was greatly reduced because of a large increase in the net renal tubular reabsorption of oxypurinol.

Effect of Amino Acids on the Excretions of Purine Bases and Oxypurinol

“…Therefore, the amino acid infusion-induced increase in the fractional clearance of oxypurinol also seems to be only attributable to increases in the plasma concentration of amino acids by the intravenous infusion of the amino acid solution. These results are compatible with the previous specula tion, suggesting that the renal transport of oxypurinol is similar to that of uric acid [18], Amino acids have been employed clinically for the treatment of several kinds of illness accompanied by hypoproteinemia, e.g., malnutri tion, chronic renal failure, or liver cirrhosis. On the other hand, allopurinol has been used for the treatment of hyperuricemia.…”

“…resulting in a decrease in the plasma concentra tion of oxypurinol. In other previous studies on the renal clearance of oxypurinol [18,19], it was demonstrated that a high-protein diet or a glucose infusion increased the uri nary excretion and the fractional clearance of oxypurinol. It was further suggested that high-protein diet-induced increases in the plasma concentrations of amino acids and/or urea or glucose infusion-induced hyperglycemia may promote the urinary excretion of oxypurinol.…”

“…18, 19], it has been demonstrated that the admin istration of pyruvic acid or glucose promotes the urinary Effect of Amino Acids on the Excretions of Purine Bases and Oxypurinol excretion of uric acid by an increase in the renal clearance of uric acid [12,19]. It was then suggested that an increase in the concentration of plasma urea may promote the uri nary excretion of uric acid [ 11,18], although the oral administration of urea does not increase the urinary excretion of uric acid [12], On the other hand, it has been demonstrated that an increase in the concentration of lac tic acid in blood decreases the urinary excretion of uric acid by a decrease in the renal clearance of uric acid [24], In the present study, amino acid infusion did not signifi cantly change the plasma concentrations of urea nitrogen, pyruvic acid, or lactic acid. In addition, although a pre vious study [19] demonstrated that the 1-hour intrave nous infusion of 500 ml of 20% glucose increased the plas ma concentration of glucose to about 20 mM, resulting in an increase in the urinary excretions of uric acid and oxy purinol, the amino acid infusion-induced increase in the plasma concentration of glucose (table 5) seems to be too small in comparison with an increase in the plasma con centration of glucose by 20% glucose infusion.…”

“…Therefore, it has been suggested that amino acids play a role in the pro tein-rich diet-induced increase in the urinary excretion of K A R fi F R © 1996 S. Karger AG. Basel l \ / -\ l \ V J c l \ 0028-2766/96/0731-004IÎ10.00/0 E-Mail kargcr(a'kargcr.ch Fax+ 41 61 306 12 34 uric acid [11,18], On the other hand, a previous study [18] demonstrated that protein-rich diets increase the uri nary excretion of oxypurinol together with uric acid, and it was suggested that amino acids and/or urea play a role in the protein-rich diet-induced increase in the urinary excretion of oxypurinol [18]. However, it has not been yet determined that only amino acids increase the urinary excretion of oxypurinol.…”

Calorie Restriction Increases P-Glycoprotein and Decreases Intestinal Absorption of Digoxin in Mice

“…Furthermore, the amount of protein in the diet can influence drug metabolism and glomerular filtration. For example, in human volunteers, a protein-restricted diet resulted in a 70% decrease in the clearance of oxipurinol and uric acid (Berlinger et al, 1985).…”