title: Characterization of post-surgical alterations in the bile duct-cannulated rat.
abstract: 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. 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. Alpha(1)-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. 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.
authors.affiliation: F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Dalila
authors.initials: D
authors.lastname: Bachir-Cherif
authors.forename: Denise
authors.initials: D
authors.lastname: Blum
authors.forename: Annamaria
authors.initials: A
authors.lastname: Braendli-Baiocco
authors.forename: Evelyne
authors.initials: E
authors.lastname: Chaput
authors.forename: Gonzalo Christiano Duran
authors.initials: GC
authors.lastname: Pacheco
authors.forename: Nicholas
authors.initials: N
authors.lastname: Flint
authors.forename: Monika
authors.initials: M
authors.lastname: Haiker
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Hoflack
authors.forename: Nicole
authors.initials: N
authors.lastname: Justies
authors.forename: Rachel
authors.initials: R
authors.lastname: Neff
authors.forename: Volkmar
authors.initials: V
authors.lastname: Starke
authors.forename: Guido
authors.initials: G
authors.lastname: Steiner
authors.forename: Charles Alexandre
authors.initials: CA
authors.lastname: Tournillac
authors.forename: Thomas
authors.initials: T
authors.lastname: Singer
authors.forename: Geneviève
authors.initials: G
authors.lastname: Ubeaud-Séquier
authors.forename: Franz
authors.initials: F
authors.lastname: Schuler
mesh_terms: D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001646:Bile / Q000378:metabolism; D001652:Bile Ducts / Q000601:surgery*; D002404:Catheterization; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D008297:Male; D023421:Models, Animal; D010599:Pharmacokinetics; D040081:Protein Array Analysis; D051381:Rats; D017208:Rats, Wistar
chemical_list: D003577:Cytochrome P-450 Enzyme System; D001219:Aspartate Aminotransferases