To provide insight into the reported reduction in the plasma clearance of
diflunisal in human
renal failure, this investigation evaluated several possible mechanisms for this effect in experimental
renal failure. Rats with
renal failure, induced by
uranyl nitrate or by ureteral
ligation, had both a lower plasma clearance and an increased apparent volume of distribution, a pattern resembling that seen in human
renal failure. Steady-state
diflunisal concentration and unbound fraction were determined in studies during a constant infusion of
diflunisal to establish the relationships of concentration, protein binding and intrinsic clearance. The infusion studies revealed that the intrinsic clearance of
diflunisal, i.e., the ability of
enzyme system(s) to metabolize the
drug, was decreased in
uremia. Also,
plasma protein binding of
diflunisal was decreased, which may explain the increase in apparent volume of distribution in uremic rats. The decreased intrinsic clearance of
diflunisal in uremic rats may be due partly to saturation of biotransformation process(es) by increasing unbound concentration as a consequence of impairment of
plasma protein binding of
diflunisal, and partly due to the diminished
enzyme activity of glucuronidation by
renal failure. The lack of an effect of the
esterase inhibitor
phenylmethylsulfonyl fluoride on the intrinsic clearance of
diflunisal in uremic rats suggested that the reduced intrinsic clearance of
diflunisal was not attributable to the systemic enzymatic hydrolysis of the
ester glucuronide.