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

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

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, t1/2( ) 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 t1/2( ) 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.