Relationship of Propranolol Pharmacokinetic Parameters with Portosystemic Shunt in CCl<sub>4</sub> - induced cirrhotic Rats

Korean J Hepatol > Volume 8(3); 2002 > Article

The Korean Journal of Hepatology 2002;8(3): 277-287.

원저 : 사염화탄소 투여 흰쥐에서 간 섬유화 진행에 따른 propranolol 의 약물동태지표와 간문맥 - 체순환 단락과의 관계 ( Original Articles : Relationship of Propranolol Pharmacokinetic Parameters with Portosystemic Shunt in CCl4 - induced cirrhotic Rats )

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

Dong Hee Koh, M.D., Geun Tae Park, M.D., Jung Mi Kim, M.D., Yeong Seop Yun, M.D., Sung Hee Lee, M.D., Dong Uk Kim, M.D., Jin Bae Kim, M.D., Yun Yung Choi, M.D.*, Ju Seop Kang, M.D.**, Ho Soon Choi, M.D., Joon Soo Hahm, M.D., Min Ho Lee, M.D.

Research Institute of Digestive Disease, Department of Nuclear Medicine*, Pharmacology** Hanyang University Collage of Medicine, Seoul, Korea

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(β), 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. (Korean J Hepatol 2002;8:277-287)

KeyWords: Propranolol, Liver cirrhosis, Pharmacokinetic parameter, Thallium scintigraphy