Glucuronidation and elimination of diflunisal in the isolated perfused rat liver: effect of pretreatment with phenobarbitone, clofibric acid and spironolactone.

The effects of pretreatment of rats with phenobarbitone, clofibric acid and spironolactone on the metabolism and biliary excretion of the salicylate derivative diflunisal have been studied using the isolated perfused liver. The clearance of diflunisal was increased significantly by pretreatment with each of the drugs. Biliary excretion of diflunisal acyl and phenolic glucuronides followed apparent first-order and Michaelis-Menten kinetics, respectively. Pretreatment with clofibric acid or spironolactone resulted in a significant increase in the biliary excretion of the phenolic glucuronide. Pretreatment with phenobarbitone or spironolactone enhanced biliary excretion of the acyl glucuronide, particularly during the first 2 hr. The concentration of the phenolic glucuronide in the perfusate increased steadily during the 6 hr perfusions, whereas the acyl glucuronide concentration was relatively stable, reflecting the ease of hydrolysis of acyl glucuronides under physiological conditions.