Use of liver slices to assess metabolic drug-drug interactions in cattle

VIRKEL G.; VIVIANI P.; QUIROGA M. ; MATÉ L.; LIFSCHITZ A.; LANUSSE C.

Nantes

Congreso; 13th International Congress of the European Association for Veterinary Pharmacology and Toxicology; 2015

INTRODUCTIONPrecision-cut liver slices (LSs) became popular for studies on the hepatic metabolism of xenobiotics since the introduction of Krumdieck? and Brendel-Vitron? tissue slicers. Culture of LSs may help to identify potential drug-drug interactions. A metabolic interaction between the anthelmintic albendazole (ABZ) and the anti-thyroid drug methimazole (MTZ) has been established both in vitro (liver microsomes) and in vivo (pharmacokinetic trials) in ruminants. In view of those previous findings, this work aims to investigate whether or not cattle LSs would be useful to test metabolic interactions, based on the well-known ability of MTZ to inhibit the hepatic metabolism of ABZ. MATERIALS AND METHODSBovine liver samples were obtained from six (6) steers. LSs (25.6±3.7 mg wet weight) were produced by operating a Brendel-Vitron? tissue slicer filled with oxygenated ice-cold Krebs buffer. Intracellular K+ (K+i) and reduced glutathione (GSH) were measured as tissue viability indicators. LSs were cultured (up to 12 h) in Williams? Medium E fortified with 50 µM of ABZ alone (control incubations) or 50 µM of ABZ plus 100 µM of MTZ. LSs were floated onto titanium roller inserts placed in glass vials containing culture medium (1.7 mL). Vials were introduced into a Vitron? dynamic organ culture incubator (DOC) set at 37°C and cultured under a humidified atmosphere (95% O2:5% CO2). Alternatively, LSs were placed in well plates (WP) containing 1.3 mL of culture medium and incubated at 37°C under the same atmosphere conditions. RESULTSK+i contents did not change throughout the 12 h culture period. A slight decrease of GSH concentrations (DOC: 24%, p