The aim of the present study was to investigate the mechanism for the stereoselective presystemic clearance of carvedilol. We examined the oxidation and glucuronidation of carvedilol in human liver microsomes (HLM) and human intestinal microsomes (HIM). The oxidation of carvedilol in HLM and HIM was evaluated in the presence of NADPH, whereas glucuronidation was evaluated in the presence of UDP-glucuronic acid. Oxidation of S-carvedilol in HLM and HIM was greater than that of R-carvedilol. In addition, the oxidation of R-carvedilol in HLM was inhibited by quinidine, whereas that of S-carvedilol was inhibited by both quinidine and furafylline. On the other hand, R-and S-carvedilol oxidation in HIM was inhibited by ketoconazole. Glucuronidation of Scarvedilol in HLM and HIM was also higher than that of R-carvedilol. These results suggested that cytochrome P450 (CYP) 2D6 and CYP1A2 are involved in the stereoselective oxidation of carvedilol in the liver, that CYP3A4 is involved in intestinal oxidation, and that glucuronidation in the liver and intestine is at least partly responsible for stereoselective presystemic clearance.

The intestinal absorption of orally administered propranolol is essentially complete, with no metabolism of this drug occurring in the gut.1,2) 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.1,3) However, Bianchetti et al. 4) showed that the area under the concentration-time curve for orally administered propranolol in renal failure patients not on hemodialysis is 7-to 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.5) 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. 5)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. 2,6) 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.6) 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. 6) 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. [6][7][8] In addition, endogenous uremic substances are not involved in the reduced hepatic extraction of metoprolol in BUL rats. 9) 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. 10) We consider that the investigation of pharmacokinetics in other renal failure models is indispensable in order to understand the ...

The hepatic extraction of metoprolol is reduced in rats with bilateral ureter ligation (BUL)-induced renal failure. The aim of the present study was to evaluate the effect of uremic substances on the hepatic metabolism of metoprolol in rats with BUL. The metabolic rate in the liver microsomes of BUL rats was similar to that in sham rats, and there was no significant difference between sham and BUL rats in the effect of the supernatant of liver homogenates on the metabolism. The rate of metabolism in the liver microsomes in the presence of the plasma of BUL rats was also similar to that in the presence of the plasma of sham rats. These findings indicated that uremic substances which accumulate in BUL rats do not directly inhibit the activity of CYP2D2, which is responsible for the metabolism of metoprolol in the rat liver.