Biol. Pharm. Bull. 28(9) 1809—1812 (2005)

nolol is essentially complete, and no metabolism of this drug occurs in the gut. After the oral administration of propranolol, the liver is the principal site of extensive pre-systemic and systemic metabolism, and less than 1% of the intact drug is found in the 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. The pharmacokinetics of propranolol has been extensively investigated using uranyl nitrate-induced renal failure model rats. These studies showed increased bioavailability and reduced hepatic first-pass extraction of propranolol in rats with renal failure, although the precise biochemical and/or physiological mechanism for the decreased presystemic clearance is unclear. Because changes in government regulations regarding the production of radioactive substances have made uranyl nitrate less available, 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 first-pass extraction of propranolol was dose-dependent and saturable in both renal failure and control rats, and the initial absorption rate of the drug from the intestine in rats with renal failure was significantly greater than that 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. The mechanism responsible for the increased bioavailability of propranolol in bilateral ureter-ligated (BUL) rats is different from that in the rats with cisplatin-induced renal failure. That is, Laganiére and Shen investigated the pharmacokinetics of intravenously and orally administered propranolol in BUL rats, and showed that the bioavailability is increased in BUL rats as compared with control rats. They reported that the gastrointestinal absorption of propranolol is not altered in BUL rats as compared with control rats. We also investigated the pharmacokinetics of propranolol in BUL rats, and confirmed that the intestinal absorption rate of propranolol in BUL rats was similar to that in control rats. Therefore, the absorption rate-dependent decrease in hepatic first-pass clearance of the drug due to saturation kinetics was marginal in BUL rats. On the other hand, we found that the blood concentrations of propranolol following intra-portal infusion in BUL rats were significantly higher than those in control rats. Therefore, the increased bioavailability of propranolol in BUL rats was attributed to diminished hepatic first-pass metabolism. The activity of CYP2D2, which is responsible for the metabolism of propranolol in the rat liver, was not altered by BUL, whereas the NADPH generation rate in the liver cytosolic fraction of BUL rats was lower than that of control rats. Accordingly, we thought that the decrease in the hepatic metabolic activity and extraction of propranolol in BUL rats is mainly a result of the reduced generation of NADPH in the liver. It is reported that the activity of glucose-6-phosphate dehydrogenase (G-6-PD), which is one of the enzymes generating NADPH in the pentose phosphate pathway, is increased in rats with bile duct ligation (BDL)-induced liver impairment. However, the mechanism responsible for the decreased NADPH generation in BUL rats is still unclear. In the present study, we compared the activity of enzymes involved in the pentose phosphate pathway in BUL rats with that in BDL rats. In addition, we also investigated the concentration of endogenous substrate(s) for NADPH-generating enzymes in BUL rats.