Abstract

A rabbit model has been used to investigate two hypotheses for the decrease in clofibric acid plasma clearance on probenecid coadministration in man. Rabbits administered probenecid (10 mg/kg followed by 10 mg/kg/hr) showed a mean reduction from control values of 68% for clofibric acid plasma clearance, 80% for clofibric acid glucuronide renal clearance and an elevation in the area under the plasma clofibric acid glucuronide concentration-time curve of 5.2-fold. These findings support the hypotheses that the decrease in clofibric acid plasma clearance involves the inhibition of the renal secretion of clofibric acid glucuronide by probenecid and the subsequent hydrolysis of the glucuronide as the major mechanism, rather than direct inhibition of clofibric acid glucuronide synthesis by probenecid, but do not exclude a mechanism in which both processes operate.