Mechanism Responsible for the Decreased Hepatic NADPH Generation Rate in Rats with Bilateral Ureter Ligation-Induced Renal Failure

Abstract

The intestinal absorption of orally administered propranolol is essentially complete, and no metabolism of this drug occurs in the gut. 1,2) 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.1,3) 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 7-to 8-fold higher than that in healthy volunteers.4) The pharmacokinetics of propranolol has been extensively investigated using uranyl nitrate-induced renal failure model rats. 5,6) 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. 7,8) 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.9) 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. 9)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.2,10) 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.2) 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. 10)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. 10) Therefore, the increased bioavailability of propranolol in BUL rats was attributed to diminished hepatic first-pass metabolism. The activity of CYP2...

Pharmacokinetics and Hepatic Extraction of Metoprolol in Rats with Glycerol-Induced Acute Renal Failure

“…22) However, there may be other possible explanations for the diminished hepatic extraction of drugs. 8,23) We reported that the decrease in the generation of NADPH in BUL rats was mainly caused by the decreased concentration of endogenous substrate(s) and/or the increased concentration of endogenous inhibitor(s) for the pentose phosphate pathway. 8) Sun et al reported that uremic toxin directly inhibited the uptake of erythromycin by rat hepatocytes, mainly by inhibiting the liver uptake transporter.…”

“…8,23) We reported that the decrease in the generation of NADPH in BUL rats was mainly caused by the decreased concentration of endogenous substrate(s) and/or the increased concentration of endogenous inhibitor(s) for the pentose phosphate pathway. 8) Sun et al reported that uremic toxin directly inhibited the uptake of erythromycin by rat hepatocytes, mainly by inhibiting the liver uptake transporter. 23) In addition, hepatic drug metabolism may be decreased in patients with renal dysfunction.…”

“…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.…”

Mechanisms responsible for the altered pharmacokinetics of Bosentan: analysis utilizing rats with bile duct ligation‐induced liver dysfunction

“…Effect of BDL and cyclosporine on the pharmacokinetics of bosentan BDL was performed according to the method reported previously [8,9]. Briefly, the abdominal cavity was opened via a midline incision under pentobarbital anesthesia, and the common bile duct was ligated twice with silk sutures.…”

Endogenous Uremic Substances are not Involved in the Reduced Hepatic Extraction of Metoprolol in Bilateral Ureter-Ligated Rats†

“…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. [10][11][12] Accordingly, we speculated that the decrease in the hepatic metabolic activity and extraction of propranolol and metoprolol in BUL rats is at least partly due to the reduced generation of NADPH in the liver.…”