Reduced clofibric acid clearance in renal dysfunction is due to a futile cycle

Although clofibric acid is cleared predominantly by formation of an ester glucuronide, its plasma clearance is reduced in renal dysfunction. The mechanism of this phenomenon has been investigated in rabbits in which uranyl nitrate administration (0.0625-0.5 mg/kg) produced a dose-dependent decrease in creatinine clearance and clofibric acid plasma clearance. Uranyl nitrate doses of 0.3 mg/kg reduced creatinine clearance by approximately 90%, clofibric acid plasma clearance by approximately 60%, clofibric acid glucuronide renal clearance by approximately 85% and increased the time averaged plasma concentration of clofibric acid glucuronide approximately by 6-fold, compared to control values. Fifty percent of administered clofibric acid glucuronide is hydrolyzed to clofibric acid in rabbits with normal renal function. These studies support a mechanism for the renal function dependent plasma clearance of clofibric acid involving a futile cycle in which the net plasma clearance of clofibric acid is determined by the conjugation of clofibric acid and competition between renal clearance and hydrolysis of the ester glucuronide.