Effect of acute renal failure on the disposition of cefoperazone

The effect of acute renal failure on the disposition of cefoperazone was investigated. Rats, 3 days after uranyl nitrate treatment, were used to model acute renal failure. Although plasma-protein binding of cefoperazone decreased significantly in acute renal failure compared with control rats, the plasma clearance of total (bound plus unbound) drug after intravenous administration (50 mg kg(-1)) did not differ significantly between the two groups (5.61+/-2.37 mL min(-1) for control and 4.75+/-2.82 mL min(-1) for acute renal failure). Consequently the plasma clearance of the unbound drug in acute renal failure (6.14+/-1.16 mL min(-1)) was significantly lower than in control rats (15.6+/-3.7 mL min(-1), P < 0.025). Plasma clearance of the drug (both total and unbound) was also dependent on bile flow, and clearance of the unbound drug in acute renal failure rats was lower than in control rats with identical bile flow rates. To examine the mechanism of reduced unbound cefoperazone clearance, an in-vitro experiment using a simultaneous perfusion system of rat liver and kidney was performed. By changing perfusate plasma protein from bovine serum albumin to human serum albumin, the plasma clearance of the total cefoperazone changed to one-sixth in proportion to the unbound cefoperazone in the perfusate plasma. On the other hand, the plasma clearance of the total and unbound drug in acute renal failure rats decreased significantly compared with controls. These results demonstrate that the plasma clearance of unbound cefoperazone, which is mainly eliminated by the liver, decreased in acute renal failure in rats, probably due to changes in hepatic transport.