[Relationship of propranolol pharmacokinetic parameters with portosystemic shunt in CCl4-induced cirrhotic rats].
OBJECTIVE
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, t1/2(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.


CONCLUSIONS
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.
Koh
Dong Hee
DH
Research Institute of Digestive Disease, Hanyang University Collage of Medicine, Seoul, Korea.
Park
Geun Tae
GT
Kim
Jung Mi
JM
Yun
Yeong Seop
YS
Lee
Sung Hee
SH
Kim
Dong Uk
DU
Kim
Jin Bae
JB
Choi
Yun Yung
YY
Kang
Ju Seop
JS
Choi
Ho Soon
HS
Hahm
Joon Soo
JS
Lee
Min Ho
MH
D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000150:complications*; D002851:Chromatography, High Pressure Liquid; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism* / Q000503:physiopathology; D011168:Portal System / Q000503:physiopathology; D011433:Propranolol / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013794:Thallium Radioisotopes
D013794:Thallium Radioisotopes; D011433:Propranolol