Effect of dose on the glucuronidation and sulphation kinetics of diflunisal in man: single dose studies

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-1 to 8.7 +/- 1.4 ml min-1 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 min-1. 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.