Renal Function Derangements Induced by Portacaval Anastomosis in Normal Rats

Romeo, José María; López‐Farré, Antonio; Martín‐Paredero, Vicente; López-Novoa, J. M.

doi:10.1159/000129152

Cited by 2 publications

(2 citation statements)

References 13 publications

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“…It has been reported that a portacaval shunt in normal rats can cause changes in renal function . Importantly, these changes were observed 30 days after the portacaval shunt was established, and the procedure did not include hepatectomy.…”

Section: Use and Limitations As Pharmacokinetic Modelsmentioning

confidence: 99%

Nephrectomized and Hepatectomized Animal Models as Tools in Preclinical Pharmacokinetics

Vestergaard¹,

Agersø

Lykkesfeldt

2013

Basic Clin Pharma Tox

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Early understanding of the pharmacokinetics and metabolic patterns of new drug candidates is essential for selection of optimal candidates to move further in to the drug development process. In vitro methodologies can be used to investigate metabolic patterns, but in general, they lack several aspects of the whole-body physiology. In contrast, the complexity of intact animals does not necessarily allow individual processes to be identified. Animal models lacking a major excretion organ can be used to investigate these individual metabolic processes. Animal models of nephrectomy and hepatectomy have considerable potential as tools in preclinical pharmacokinetics to assess organs of importance for drug clearance and thereby knowledge of potential metabolic processes to manipulate to improve pharmacokinetic properties of the molecules. Detailed knowledge of anatomy and surgical techniques is crucial to successfully establish the models, and a well-balanced anaesthesia and adequate monitoring of the animals are also of major importance. An obvious drawback of animal models lacking an organ is the disruption of normal homoeostasis and the induction of dramatic and ultimately mortal systemic changes in the animals. Refining of the surgical techniques and the post-operative supportive care of the animals can increase the value of these models by minimizing the systemic changes induced, and thorough validation of nephrectomy and hepatectomy models is needed before use of such models as a tool in preclinical pharmacokinetics. The present MiniReview discusses pros and cons of the available techniques associated with establishing nephrectomy and hepatectomy models.

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Section: Use and Limitations As Pharmacokinetic Modelsmentioning

confidence: 99%

Nephrectomized and Hepatectomized Animal Models as Tools in Preclinical Pharmacokinetics

Vestergaard¹,

Agersø

Lykkesfeldt

2013

Basic Clin Pharma Tox

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“…In liver diseases that result in fibrosis and portal hypertension, angiogenesis can result in the shunting of blood from the portal vein to the systemic circulation; this is referred to as portacaval anastomosis. In human liver cirrhosis, the surgical shunting of portal blood relieves backpressure and prevents further organ and vascular damage (Romeo et al 1990(Romeo et al , 1991. Among the major complications of cirrhosis and portacaval anastomosis are hyperammonemia and hepatic encephalopathy (Olde Damink et al 2002).…”

Section: Introductionmentioning

confidence: 99%

The effect of portacaval anastomosis on the expression of glutamine synthetase and ornithine aminotransferase in perivenous hepatocytes

Silva

Levillain

Brosnan

et al. 2013

Can. J. Physiol. Pharmacol.

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There is functional zonation of metabolism across the liver acinus, with glutamine synthetase restricted to a narrow band of cells around the terminal hepatic venules. Portacaval anastomosis, where there is a major rerouting of portal blood flow from the portal vein directly to the vena cava bypassing the liver, has been reported to result in a marked decrease in the activity of glutamine synthetase. It is not known whether this represents a loss of perivenous hepatocytes or whether there is a specific loss of glutamine synthetase. To answer this question, we have determined the activity of glutamine synthetase and another enzyme from the perivenous compartment, ornithine aminotransferase, as well as the immunochemical localization of both glutamine synthetase and ornithine aminotransferase in rats with a portacaval shunt. The portacaval shunt caused a marked decrease in glutamine synthetase activity and an increase in ornithine aminotransferase activity. Immunohistochemical analysis showed that the glutamine synthetase and ornithine aminotransferase proteins maintained their location in the perivenous cells. These results indicate that there is no generalized loss of perivenous hepatocytes, but rather, there is a significant alteration in the expression of these proteins and hence metabolism in this cell population.

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Renal Function Derangements Induced by Portacaval Anastomosis in Normal Rats

Cited by 2 publications

References 13 publications

Nephrectomized and Hepatectomized Animal Models as Tools in Preclinical Pharmacokinetics

Nephrectomized and Hepatectomized Animal Models as Tools in Preclinical Pharmacokinetics

The effect of portacaval anastomosis on the expression of glutamine synthetase and ornithine aminotransferase in perivenous hepatocytes

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