ABSTRACT
BACKGROUND: This study was designed to determine the relationship of propranolol pharmacokinetic parameters with portosystemic shunt in CCl4-induced cirrhotic rats. METHODS: Cirrhotic rats(n=6) were induced by intramuscular injection of CCl4 in olive oil(two time per weeks) for 12 weeks. Controls (n=6) were injected intramuscularly with the same dose of olive oil for 12 weeks. We evaluated the amount of portosystemic shunt by thallium-201 per rectal scintigraphy. After intravenous bolus injection of propranolol (2mg/kg) to rats, the serum propranolol concentrations were analyzed by a HPLC-fluorimetric detector system. Pharmacokinetic parameters such as C0, AUC, t(1/2(beta)), and CLp were determined in each group. Then, a small amount of heptic tissue was obtained and subjected to determination of the hepatic collagen content by quantitating 4-hydroxyproline and were inspected by microscope after hematoxylin and eosin stain. RESULTS: In liver biopsy, liver fibrosis progressed in CCl4-induced cirrhotic rats. The serum concentrations of propranolol were significantly (p < 0.01) elevated in CCl4-induced cirrhotic rats. Mean amount of 4-hydroxyproline, mean H/L ratio, and mean AUC in CCl4-induced cirrhotic rats was significantly (p < 0.01) higher than that in control rats. There was a relationship between AUC, H/L ratio, and amount of 4-hydroxyproline. CONCLUSION: H/L ratio may help in the selection of drug dosage (especially blood flow dependent drug) in pre-clinical studies for chronic liver disease during the drug development process.
Subject(s)
Animals , Rats , Carbon Tetrachloride Poisoning/complications , Chromatography, High Pressure Liquid , English Abstract , Liver Cirrhosis, Experimental/metabolism , Portal System/physiopathology , Propranolol/pharmacokinetics , Rats, Sprague-Dawley , Thallium RadioisotopesABSTRACT
BACKGROUND/AIMS: It is well known that alcohol enhances the toxicity of CCl4. We tried to establish an alcoholic liver cirrhosis model by administration of alcohol and CCl4 to rats. We also wanted to know the hepatoprotective effect of low doses of lipopolysaccharide(LPS) in this animal model. METHODS: Of 20 female adult rats, 8 were ingested with alcohol ad libitum(group 1) Another 6 were ingested with 10% alcohol and 50% 1mL/kg CCl4 intragastrically by Sonde twice a week(group 2) The remaining 6 were ingested with 10% alcohol, CCl4, and 0.1mg/kg LPS intraperitoneally twice a week(group 3) The fibrosis was evaluated semiquantitatively on a scale of 0(none) to 3(cirrhosis). RESULTS: 1) After 10 weks, septal fibrosis or cirrhosis was produced in 9 out of 12 rats in groups 2 and 3 but there was no fibrotic change in group 1. 2) There was no significant difference in pathological grading between groups 2 and 3. CONCLUSIONS: Hepatic fibrosis or cirrhosis can be sufficiently induced by alcohol and repetitive CCl4 ingestion for 10 weeks. We can not prove the hepatoprotective effect of low dose LPS by semiquantitative evaluation of pathological grading.
Subject(s)
Animals , Female , Rats , Carbon Tetrachloride Poisoning/complications , English Abstract , Ethanol/toxicity , Lipopolysaccharides/administration & dosage , Liver/pathology , Liver Cirrhosis, Alcoholic/pathology , Rats, Sprague-DawleyABSTRACT
Liver damage induced in rats by carbon tetrachloride (CCL4) was obvious macroscopically as well as microscopically in stained sections. Levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma glutamyl transpeptidase (gamma-GT) were also significantly raised. Adenosine and inosine effectively countered the damage when these were given before and during the period during which CCl4 produces the typical damage. The beneficial effect was seen in biochemical as well as pathological studies.
Subject(s)
Adenosine/therapeutic use , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , Carbon Tetrachloride Poisoning/complications , Hemorrhage/chemically induced , Inosine/therapeutic use , Liver/drug effects , Liver Diseases/chemically induced , Male , Rats , Rats, Inbred Strains , gamma-Glutamyltransferase/bloodABSTRACT
Carbon tetrachloride (CCl4) brings about a rise in cytosolic free calcium which may lead to glycogen mobilization. Therefore, glycogen and glucose-6-phosphatase (G-6-pase) levels in the liver of parathyroidectomized (PTX) rats following CCl4 treatment have been estimated. CCl4 depletes both glycogen and G-6-pase levels in the liver. PTX followed by CCl4 administration, however, fails to restore liver glycogen and G-6-pase levels. The results suggest that neither cytosolic Ca2+ nor phospholipase A2 mediation is needed for glycogen mobilization, however, glucocorticoid intervention might have a role in such mechanisms.