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 intraperitoneally to rabbits during 8 weeks to induce a model of liver insufficiency. All animals developed pericentrolobular fibrosis. The intensity of the fibrosis was proportional to the dose. An increase in the plasma enzymatic activities (ALAT, ASAT, gamma GT) was related to the dose. 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 enzymatic activity, whereas no change was observed in UDP glucuronyltransferase activity. When antipyrine was administered to the intragastric group, a reduction of total body clearances and an increase in half-lives 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. With the exception of the intragastric dose of 0.035 mL/kg, the pharmacokinetics of indocyanine green showed a decrease in total body clearances and an increase in areas under the curve. Distribution volumes decreased 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 indicate that rabbits chronically intoxicated with CCl4 may be an adequate model for studying the influence of hepatic insufficiency on pharmacokinetic disposition.
Delrat
P
P
Laboratoire de Pharmacologie-Pharmacocinétique, Faculté des Sciences Pharmaceutiques, CHU Purpan, Toulouse, France.
Dupin
S
S
Galtier
P
P
Alvinerie
M
M
Voigt
J J
JJ
Tufenkji
A E
AE
Saivin
S
S
Houin
G
G
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000983:Antipyrine / Q000493:pharmacokinetics; D001219:Aspartate Aminotransferases / Q000097:blood; D001711:Biotransformation; D002252:Carbon Tetrachloride Poisoning / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D003600:Cytosol / Q000201:enzymology; D004195:Disease Models, Animal; D006207:Half-Life; D066298:In Vitro Techniques; D007208:Indocyanine Green; D008099:Liver / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D011817:Rabbits; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D007208:Indocyanine Green; D000983:Antipyrine