Background/Aims
This study was designed to determine the effect of hepatic fibrotic severity on pharmacokinetics of propranolol in CCl₄-treated rats.Methods:1 mL/kg of 10% CCl₄ in olive oil was injected intramuscularly to rats twice weekly for 4, 6, 8 and 10 weeks, respectively(n=6). Control(n=6) was a sham-injected equal dose of olive oil for 10 weeks. After intravenous bolus injection of 2 mg/kg propranolol to rats, the serum propranolol concentrations were analyzed for 4 hours at various time points by a HPLC-fluorimetric system, and pharmacokinetic parameters such as C₀, MRT, AUC, Vdss, t_1/2(β) and CLp were determined. Then, a small amount of hepatic tissue was obtained and subjected to determination of the hepatic 4-hydroxyproline content, which confirmed the hepatic fibrotic severity. Results:The serum concentrations of propranolol at 0.5, 1, 2 and 4 hours were significantly increased in CCl₄-treated rats(p<0.01). In proportion to the duration of CCl₄ treatment, C₀ and AUC were significantly increased, and Vdss and CLp were significantly decreased(p<0.001). But MRT and t_1/2(β) were not significantly changed. The hepatic 4-hydroxyproline content was gradually increased in CCl₄-treated rats(p<0.001).Conclusion:Gradual changes in pharmacokinetic parameters of propranolol were seen to be dependent on the hepatic fibrotic severity. We suggest that gradual dosage modification, according to their hepatic fibrotic severity, is necessary for many drugs administered to patients with chronic liver disease.(Korean J Hepatol 2001;7:181-188)

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)