Korean J Hepatol.  2002 Sep;8(3):277-287.

Relationship of Propranolol Pharmacokinetic Parameters with Portosystemic Shunt in CCl4-induced cirrhotic Rats

• Koh DH
• Park GT
• Kim JM
• Yun YS
• Lee SH
• Kim DU
• Kim JB
• Choi YY
• Kang JS
• Choi HS
• Hahm JS
• Lee MH

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.

Keyword

Propranolol; Liver cirrhosis; Pharmacokinetic parameter; Thallium scintigraphy

MeSH Terms

Animals
Carbon Tetrachloride Poisoning/*complications
Chromatography, High Pressure Liquid
English Abstract
Liver Cirrhosis, Experimental/*metabolism/physiopathology
Portal System/physiopathology
Propranolol/*pharmacokinetics
Rats
Rats, Sprague-Dawley
Thallium Radioisotopes/diagnostic use