The single-dose plasma kinetics of
diflunisal was studied in healthy young and old subjects, in patients with
rheumatoid arthritis, and in patients with
renal failure. The plasma and urine kinetics of the glucuronidated metabolites of
diflunisal were studied in the healthy elderly subjects and in the patients with
renal failure. In addition, the multiple-dose plasma kinetics of
diflunisal was assessed in healthy volunteers and in patients with
rheumatoid arthritis. After a single dose of
diflunisal the terminal plasma half-life, mean residence time and apparent volume of distribution were higher in elderly subjects than in young adults. No difference was observed in any pharmacokinetic parameter between age-matched healthy subjects and patients with
rheumatoid arthritis. The elimination half-life of unchanged
diflunisal was correlated with the
creatinine clearance (r = +0.89) and its apparent total body clearance exhibited linear dependence on
creatinine clearance (r = +0.78). In patients with
renal failure, the terminal plasma half-life and mean residence time of
diflunisal were prolonged. The renal and apparent total body clearances were lower, the mean apparent volume of distribution was higher and the mean area under the concentration-time curve extrapolated to infinity (AUC) was greater in the
renal failure patients than in controls. The plasma concentration of the glucuronidated metabolites rapidly rose to levels above those of unchanged
drug in renal patients, whereas they were lower than those of unchanged
diflunisal in controls. The AUC (0-96 h) of
diflunisal glucuronides in the patients was four-times that in controls, and the terminal elimination half-life of the
glucuronides was prolonged in them. The renal excretion and clearance of
diflunisal glucuronides were reduced when renal function was impaired. After multiple dosing, the pre-dose steady-state plasma-concentration increased with decreasing
creatinine clearance (r = -0.79). When the plasma concentration exceeded 200 mumols.l-1, the elimination half-life was doubled, due to partial saturation of
diflunisal conjugation. This finding suggests that lower doses could be used in long-term treatment. Thus, old age and arthritic disease appear to have little influence on the kinetics of
diflunisal in the absence of renal functional impairment. Ordinary doses can be given for short term treatment of elderly patients with or without RA. In patients with
renal failure, however, reduced doses of
diflunisal are recommended.