Sustained reductions in oxipurinol renal clearance during a restricted diet

Abstract

The renal clearance of oxipurinol, the major metabolite of allopurinol, was studied in six healthy subjects during normal and restricted (low protein and low calorie) diets. A 600 mg oral dose of allopurinol was administered after 7 days of a normal diet (100 mg protein/day) and again after 2 and 4 weeks of a restricted diet (19 gm protein/day). The renal clearance of oxipurinol was reduced from 19.6 +/- 1.5 ml/min during the normal diet to 10.9 +/- 0.8 and 12.0 +/- 0.9 ml/min (both P less than 0.001) during the restricted diet at 2 and 4 weeks, respectively. These changes in oxipurinol renal clearance paralleled changes in uric acid renal clearance. Furthermore, the plasma oxipurinol half-life was increased from 27.0 +/- 1.7 hours during the normal diet to 51.1 +/- 4.3 and 45.7 +/- 3.7 hours (both P less than 0.001) during the restricted diet at 2 and 4 weeks, respectively. We conclude that dietary protein and calorie restriction cause a sustained reduction in the elimination of oxipurinol.

Effect of Dietary Protein on Renal Tubular Clearance of Drugs in Humans

“…In 3 of our studies we measured acetoacetate and fJ-hydroxybutyrate concentrations to evaluate ketone bodies as competitive inhibitors of uric acid and oxipurinol renal elimination (Kitt et al 1988(Kitt et al , 1989Park et al 1987). Our data do not support the hypothesis that elevation of plasma ketone bodies during the low-protein diet explained the reduction in renal clearance of those compounds.…”

“…Our data do not support the hypothesis that elevation of plasma ketone bodies during the low-protein diet explained the reduction in renal clearance of those compounds. Although plasma ketone bodies increased by almost a factor of 3 during the protein-and calorierestricted diet, previous studies suggested that 60-to 80-fold elevations were required to reduce uric acid renal clearance (Goldfinger et al 1985;Park et al 1987). However, even stronger evidence was produced in our study of isocaloric diets that showed that the changes in renal clearance of oxipurinol and uric acid occur in the absence of any change in plasma ketone bodies (Kitt et al 1988).…”

“…Previous work by Bowering et al (1970) had demonstrated this with uric acid, and we confirmed the relation- Table II. Mean (± SEM; n = 6) pharmacokinetic data on allopurinol 600mg and oxipurinol during a normal diet· and after 2 and 4 weeks of a low-protein diet (after Park et al 1987 Oxipurinol CLR (ml/min/70kg) Fig. 1.…”

“…= 268g protein; • = 100g; D, 0 = 199) and the renal clearances of uric acid and oxipurinol. Data represent the mean (± SE) of the uric acid and oxipurinol renal clearances per 70kg bodyweight from 2 studies (Berlinger et al 1985;Park et al 1987). …”