Characterization of post-surgical alterations in the bile duct-cannulated rat

Abstract

1. The bile duct-cannulated (BDC) rat is a standard animal model used in ADME experiments. The aim of this study was to investigate post-surgical alterations that are relevant to ADME investigations in BDC rats compared with sham- and non-operated animals.

2. Water and food intake was reduced in the animals’ post-surgery. This led to a lower body weight in operated animals. In BDC animals, aspartate aminotransferase (AST) levels in plasma were transiently elevated and total bile acid levels were reduced. Alpha₁-acid glycoprotein (AGP) in plasma and the concentration of bile components in bile were elevated. Histopathology showed inflammation in the area of the cannulation between the liver and the small intestine. A microarray-based gene expression and RTq-PCR analysis identified altered expression for several genes involved in drug disposition including the down-regulation of cytochrome P450 enzymes. This led to reduced cytochrome P450 content in the liver and lower metabolic activity in microsomes from BDC and sham-operated rats compared with naïve animals.

3. The results of the study suggest that the post-surgical inflammation leads to physiological changes relevant for drug absorption and disposition. These alterations should be accounted for in the interpretation of ADME studies in BDC animals.

Keywords::

• Pharmacokinetics
• bile duct cannulation
• rat

Acknowledgements

The authors would like to thank Véronique Dall’Asen, Marie Stella Gruyer, Christelle Rapp, Aynur Ekiciler, Katrin Schliemann, Martin Mangold, Christiane Wohlgensinger and Andreas Staempfli for technical support. They would also like to thank Stephen Fowler, Martin Kapps and Juerg Marty for valuable discussions on the topic and James Zimmerman and Zoe Goodger for proof reading of the manuscript.

Declaration of interest

This work was funded by F. Hoffmann-La Roche Ltd. in Basel, Switzerland and was supported by the University of Strasbourg, France. The authors report no declarations of interest.