ASSESSMENT OF HEPATIC INSUFFICIENCY MODEL IN THE RABBIT USING CARBON-TETRACHLORIDE INTOXICATION

The objective of the present study was to compare two doses (0.035 and 0.1 mL/kg) of carbon tetrachloride given intragastrically or intraper itoneally to rabbits during 8 weeks to induce a model of liver insuffi ciency. All animals developed pericentrolobular fibrosis. The intensit y of the fibrosis was proportional to the dose. An increase in the pla sma enzymatic activities (ALAT, ASAT, gamma GT) was related to the dos e. Plasma proteins and creatinine levels remained unaltered during the experiment. Hepatic microsomal cytochrome P450 was reduced in treated animals in relation to the dose, as was glutathione-S-transferase enz ymatic activity, whereas no change was observed in UDP glucuronyltrans ferase activity. When antipyrine was administered to the intragastric group, a reduction of total body clearances and an increase in half-li ves and areas under the curve were observed in relation to a reduction of oxidation capacities. After intraperitoneal intoxication, only the total body clearance with a 0.1 mL/kg dose increased significantly. W ith the exception of the intragastric dose of 0.035 mL/kg, the pharmac okinetics of indocyanine green showed a decrease in total body clearan ces and an increase in areas under the curve. Distribution volumes dec reased in treated animals whereas half-lives remained constant. After an intragastric dose of 0.035 mL/kg, only an increase in half-life and a decrease in total body clearance were observed. All these results i ndicate that rabbits chronically intoxicated with CCl4 may be an adequ ate model for studying the influence of hepatic insufficiency on pharm acokinetic disposition.