1 The single (250 and 500 mg) and multiple dose (250 and 500 mg twice daily for 15 days) pharmacokinetics of diflunisal were compared in young volunteers. 2 The plasma clearance of diflunisal was lowered significantly after multiple dose administration (5.2 ± 1.2 and 4.2 ± 0.7 ml min-' for the 250 and 500 mg twice daily regimens, respectively) as compared with single dose administration (11.4 ± 3.1 and 9.9 + 2.0 ml min-' for the 250 and 500 mg single doses, respectively).3 The partial metabolic clearances of diflunisal by acyl and phenolic glucuronide formation were lowered significantly (> 50%) after multiple dose administration. 4 The urinary recovery of diflunisal sulphate increased as a function of dose: 6.1 ± 2.8 and 9.1 ± 3.5% following the 250 and 500 mg single dose, respectively, and 10.9 ± 3.1 and 15.9 ± 3.6% following the 250 and 500 mg twice daily regimens. The partial metabolic clearance of diflunisal by sulphate conjugation was unchanged following multiple dose administration. 5 The plasma protein binding of diflunisal was concentration-dependent. Analysis of unbound plasma clearances of diflunisal showed that its total plasma clearance following 500 mg twice daily was affected by both saturable glucuronidation and concentrationdependent plasma binding.

1. A new metabolite of diflunisal, a hydroxy derivative, has been identified in rat and human urine following administration of diflunisal. 2. This hydroxy metabolite of diflunisal is excreted in urine of both species as a polar conjugate, most likely a sulphate. 3. Attempts to isolate the polar conjugate in pure form were unsuccessful due to its rapid hydrolysis in the presence of acid, and organic solvents such as diethyl ether. Its breakdown product, however, was more stable and was isolated and purified by semi-preparative h.p.l.c. Unequivocal identification as 3-hydroxy-diflunisal (i.e. hydroxylation in position 3 of the salicylic acid ring) was accomplished by means of FAB-mass spectrometry and n.m.r. spectroscopy. 4. The contribution of this oxidative metabolic pathway to the overall elimination scheme of diflunisal is more important in rat than in man. Gunn rats excrete more of the hydroxy diflunisal conjugate in urine (20-30% of a 50 mg/kg i.v. dose of diflunisal) than Wistar rats. In healthy humans, hydroxylation of diflunisal contributes only to a small extent to the overall biotransformation of diflunisal.