Changes of Propranolol Pharmacokinetic Parameters According to Hepatic Fibrotic Severity in CCl<sub>4</sub>-Treated Rats

Korean J Hepatol > Volume 7(2); 2001 > Article

The Korean Journal of Hepatology 2001;7(2): 181-188.

원저 : 사염화탄소 투여 흰쥐에서 간섬유화 진행에 따른 Propranolol 의 약동학적 지표들의 변화 ( Changes of Propranolol Pharmacokinetic Parameters According to Hepatic Fibrotic Severity in CCl4-Treated Rats )

Changes of Propranolol Pharmacokinetic Parameters According to Hepatic Fibrotic Severity in CCl₄-Treated Rats

Mun Su Kang, M.D., Chang Ok Yoon, M.D., Jai Won Byun, M.D., Oh Young Lee, M.D. Byung Chul Yoon, M.D., Joon Soo Hahm, M.D., Ju Seop Kang, M.D.*, Min Ho Lee, M.D.

Research Institute of Digestive Disease, Department of Pharmacology* Hanyang University College of Medicine

ABSTRACT

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)

KeyWords: Hepatic fibrosis, Propranolol, Pharmacokinetic parameter, Hydroxyproline