Diisopropylfluorophosphate increases clofibric acid clearance: supporting evidence for a futile cycle

Clofibric acid has been shown previously to undergo a futile cycle in which its net clearance is dependent upon conjugation to form an acyl (ester) glucuronide and a combination of hydrolysis of the conjugate and its renal clearance. If hydrolysis is mediated by esterases then inhibition of these enzymes should increase clofibric acid clearance. Plasma clofibric acid clearance was measured in a group of six rabbits both while conscious and then while anesthetized and treated with diisopropylfluorophosphate (DFP). Clofibric acid clearance also was determined in a control group of six rabbits both while conscious and subsequently while anesthetized. Plasma clearances of unbound and total clofibric acid (protein bound plus unbound) were similar in both groups while conscious but increased 2-fold in DFP-treated compared with conscious animals (P less than .001) and were 3-fold greater in DFP-treated animals than in control, anesthetized animals (P less than .001). These data support the futile cycle for clofibric and implicate esterases in the in vivo hydrolysis of clofibric acid glucuronide.