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

Taguchi, Masato; Urai, Misato; Taira, Shigehiro; Tanabe, Hiroko; Hashimoto, Yoshiaki

doi:10.2133/dmpk.21.156

Drug Metabolism and Pharmacokinetics

2006

DOI: 10.2133/dmpk.21.156

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

Masato Taguchi

Misato Urai

Shigehiro Taira

et al.

Abstract: 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 … Show more

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“…It has been observed that the hepatic extraction of some clinical important drugs is significantly decreased in rats with obstructive nephropathy. [4][5][6] Despite this, the effects of obstruction of the ureters on liver function remain a limited area of knowledge.…”

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confidence: 99%

Hepatic and renal expression of Oatp1 in obstructive uropathy. First detection of Oatp1 in urine, a potential biomarker

Campagno

Nosetto

Brandoni

et al. 2021

Clin Exp Pharma Physio

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Obstructive nephropathy is a relatively common urological problem, which can occur as a consequence of a variety of conditions, such as abnormal ureteral structures, polyps, vesicoureteral reflux or nephrolithiasis. The obstruction of both ureters is a situation especially severe because of its physiological consequences; excessive salt and water loss, urine concentrating defects and alterations in the tubular handling of metabolites of endogenous and exogenous origin. [1][2][3] The renal excretion pathway of many drugs may be compromised during obstructive nephropathy. Although the liver may complement the depurating function of the kidneys, becoming an alternative pathway for the elimination of specific compounds, the relationship between renal and hepatic excretion routes depend on the structural and functional integrity of both organs. It has been observed that the hepatic extraction of some clinical important drugs is significantly decreased in rats with obstructive nephropathy. [4][5][6] Despite this, the effects of obstruction of the ureters on liver function remain a limited area of knowledge.

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mentioning

confidence: 99%

Hepatic and renal expression of Oatp1 in obstructive uropathy. First detection of Oatp1 in urine, a potential biomarker

Campagno

Nosetto

Brandoni

et al. 2021

Clin Exp Pharma Physio

View full text Add to dashboard Cite

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

Tanabe

Taira

Taguchi

et al. 2007

Biological & Pharmaceutical Bulletin

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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 ...

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Pharmacokinetics and Pharmacodynamics of Bisoprolol in Rats with Bilateral Ureter Ligation-induced Renal Failure

Tahara

Saigusa

Yuka

et al. 2006

Drug Metabolism and Pharmacokinetics

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The effect of renal failure on the pharmacokinetics and pharmacodynamics of bisoprolol was investigated in bilateral ureter-ligated (BUL) rats. The blood bisoprolol concentrations following 30-min intravenous infusion at a rate of 60 microg/kg/min were higher in renal artery-occluded (RAO) rats than in control rats, and were higher in BUL rats than in RAO rats. Increased blood bisoprolol concentrations accompanied decreased mean systemic clearances: 50.7, 36.4, and 26.2 mL/min/kg in control, RAO, and BUL rats, respectively. The finding indicated that approximately 30% of administered bisoprolol was excreted via the kidney, and that not only the renal clearance but also non-renal clearance of bisoprolol was decreased in BUL rats. The beta-blocking action of bisoprolol was assessed by the reduction in isoproterenol-induced increases in the heart rate. The relationship between blood concentration and the beta-blocking action of bisoprolol in BUL rats was similar to that in control rats. These results suggested that renal excretion and hepatic metabolism of bisoprolol were significantly reduced in BUL rats, but that pharmacodynamics of bisoprolol was not altered by acute renal failure.

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

Cited by 3 publications

References 32 publications

Hepatic and renal expression of Oatp1 in obstructive uropathy. First detection of Oatp1 in urine, a potential biomarker

Hepatic and renal expression of Oatp1 in obstructive uropathy. First detection of Oatp1 in urine, a potential biomarker

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

Pharmacokinetics and Pharmacodynamics of Bisoprolol in Rats with Bilateral Ureter Ligation-induced Renal Failure

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