1 The effect of dose (100 mg, 250 mg, 500 mg, 750 mg and 1000 mg) on the glucuronidation and sulphation of diflunisal was studied in six healthy volunteers. 2 Total urinary recovery ranged from 78.9 ± 11.9% to 91.5 ± 18.7% of the administered dose. Urinary recovery (normalized for total urinary recovery) of diflunisal sulphate (DS) significantly increased with dose from 9.3 ± 3.7% to 18.1 ± 4.8%.3 Normalized urinary recovery for diflunisal phenolic glucuronide (DPG) was unaffected by dose (range: 30.6 ± 3.8% to 40.6 ± 6.6%). Normalized urinary recovery for the acyl glucuronide (DAG) significantly decreased from 52.3 ± 4.6% to 40.2 ± 3.4% as the dose increased.4 Total plasma clearance of diflunisal significantly decreased from 14.4 ± 1.4 ml min-lto 8.7 ± 1.4 ml min-t as the dose increased from 100 mg to 750 mg. A further increase in dose to 1000 mg resulted in an unexplained increase in total plasma clearance to 10.3 ± 1.8 ml * -1 mmn 5 Dose-dependent plasma clearance of diflunisal was caused mainly by saturation of the formation of DAG, whereas the formation of DS and DPG were relatively unaffected by dose.

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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.