Biol. Pharm. Bull. 30(3) 552—555 (2007)

nolol is essentially complete, with no metabolism of this drug occurring in the gut. After the oral administration of propranolol, the liver is the principal site of extensive presystemic and systemic metabolism, and less than 1% of the intact drug is found in urine. However, Bianchetti et al. showed that the area under the concentration–time curve for orally administered propranolol in renal failure patients not on hemodialysis is 7to 8-fold higher than that in healthy volunteers. We investigated the mechanisms responsible for the increased bioavailability of propranolol in rats with cisplatin-induced renal failure. The hepatic intrinsic clearance of propranolol was not significantly altered in rats with renal failure as compared with control rats. However, hepatic firstpass extraction of propranolol was dose-dependent and saturable in both renal failure and control rats, and the initial rate of absorption of the drug from the intestine was significantly greater in rats with renal failure than in control rats. Accordingly, the increased bioavailability of propranolol in rats with cisplatin-induced renal dysfunction is mainly a result of the increased initial absorption rate in the intestine followed by the partial saturation of hepatic first-pass metabolism. Interestingly, the mechanism responsible for the increased bioavailability of propranolol in bilateral ureter-ligated (BUL) rats is different from that in rats with cisplatin-induced renal failure. We investigated the pharmacokinetics of propranolol and metoprolol in BUL rats, and found that the rate of intestinal absorption of these drugs was only slightly greater than that in control rats. On the other hand, the arterial blood concentrations of propranolol and metoprolol following intra-portal infusion were significantly higher in BUL rats than control rats. Therefore, the increased bioavailability of propranolol and metoprolol in BUL rats was attributed to diminished hepatic first-pass metabolism. The activity of CYP2D2, which is responsible for the metabolism of propranolol and metoprolol in the rat liver, was not altered by BUL, whereas the rate at which NADPH was generated in the liver cytosolic fraction was lower in BUL than control rats. In addition, endogenous uremic substances are not involved in the reduced hepatic extraction of metoprolol in BUL rats. Accordingly, the decrease in the hepatic metabolic activity and extraction of propranolol and metoprolol in BUL rats is mainly due to the reduced generation of NADPH in the liver. Since the sequence and relative importance of pathophysiological components of acute renal failure in patients are not clearly defined, it is difficult to determine which experimental method for producing renal failure in animals yields results that are most representative of the clinical condition. We consider that the investigation of pharmacokinetics in other renal failure models is indispensable in order to understand the main mechanism for the increased bioavailability of drugs in renal failure. Glycerol-induced acute renal failure (ARF) in rats is a model of acute trauma in which intramuscular injection of 50% glycerol causes rapid myoglobinuria, oliguria, and a rapid reduction in glomerular filtration rate. The effect of renal dysfunction on the pharmacokinetics and pharmacodynamics of drugs has been extensively investigated by use of glycerol-induced ARF rats. However, the effect of glycerol-induced ARF on hepatic drug metabolism is unclear. The aim of this study was to evaluate the effect of glycerol-induced ARF on the pharmacokinetics and hepatic extraction of metoprolol.