Background and objectives: Carvedilol is a drug of choice in treatment of portal hypertension. The present study was designed to elucidate the potential role of antifibrotic effects of carvedilol in improving hepatic efficiency and the carvedilol oral pharmacokinetic changes during induction of liver fibrosis.
Methods: Rats were given CCl4 (1 ml/kg, intraperitoneal) twice weekly for 6 weeks and/or co-treated with carvedilol (10 mg/kg, orally) three times weekly on alternating days. Indocyanine green (ICG) clearance test was used as a modality for the measurement of hepatic blood flow. In addition, assessment of serum albumin as a marker of synthetic capacity and immunohistochemical staining of P-glycoprotein (P-gp) expression as a marker of metabolic capacity were done. Furthermore, hydroxyproline and TGF-β1 were detected as markers of liver fibrosis.
Results: The area under plasma concentration-time curve of a single dose of carvedilol was significantly increased, associated with decreased the clearance in rats intoxicated with CCl4 compared to control group. Carvedilol co-treatment in CCl4-intoxicated rats for 6 weeks significantly counteracted the changes in hepatotoxicity markers and histopathological lesions induced by CCl4. In addition, there were no significant alterations in carvedilol pharmacokinetics between control and CCl4-intoxicated rats. Furthermore, carvedilol treatment restored liver efficiency, including synthetic and metabolic capacity as well as hepatic blood flow.
Conclusion: The present study provides evidence underlying the antifibrotic effects of carvedilol and enhancement of hepatic efficiency. In addition, the pharmacokinetic parameters of a single dose of carvedilol are altered in liver fibrosis, manifested as delayed clearance. This was attributed to the reduction of both hepatic blood flow and CYP2D6 expression in the liver. Carvedilol co-treatment in CCl4-intoxicated rats for 6 weeks recovered its pharmacokinetic profile, which is mainly attributed to the impact of pharmacodynamic antifibrotic effects of carvedilol on its own kinetics.
Keywords: CCl4; Carvedilol; Dansyl Chloride; Hepatic Blood Flow; Liver Fibrosis.