Biotransformation of diflunisal and renal excretion of its glucuronides in renal insufficiency

Abstract

1 A single oral dose of 500 mg diflunisal was administered to control subjects and patients with varying degrees of renal insufficiency to estimate the disposition kinetics of this drug.

2 Diflunisal and the sum of its ester and ether glucuronides conjugates were measured fluorimetrically.

3 In normals terminal plasma half-lives (T_½β) of diflunisal and its glucuronides were very similar: 10.8 h and 11.8 h respectively. The finding that plasma half-life was shortened with declining diflunisal plasma levels suggests capacity-limited elimination.

4 In subjects with normal renal function 78.6 ± 2.7% of the administered dose was recovered in 72 h urine, mainly as the glucuronide conjugates.

5 With increasing degree of renal function impairment T_½β of diflunisal was progressively prolonged up to ten times normal probably due to slowed biotransformation. This was associated with increasing retention of the conjugated metabolites in plasma due to marked reduction of the urinary excretion of the glucuronide conjugates.

6 The apparent volume of distribution of diflunisal was very small in normals (7.3 ± 0.4 l) and was significantly increased in patients with renal insufficiency (up to 16.2 ± 2.2 l).

7 Diflunisal elimination studies performed during haemodialysis did not reveal any significant change in diflunisal plasma half-time. In vivo ultrafiltration studies during haemodialysis have shown that diflunisal is 98-99% plasma protein bound in uraemic patients.

8 The present study indicates that although diflunisal is primarily eliminated by biotransformation, T_½β is prolonged in renal insufficiency and dose adjustment will accordingly be required in patients with renal function impairment.