Objective: The objective of this study was to investigate the synergistic antifibrotic effect of verapamil and interferon-γ (IFN-γ) on rat liver fibrosis and its potential pharmacokinetic-based mechanism.
Methods: Rat liver fibrosis model was successfully established, and both the therapeutic effects and pharmacokinetic parameters of verapamil were evaluated after the administration of verapamil with or without IFN-γ. The activities of cytochrome P450 3A (CYP3A) and the expression of multidrug resistance (Mdr) mRNA were measured in liver and small intestine.
Results: The results showed the synergistic antifibrotic effect of verapamil and IFN-γ in rat liver fibrosis, in terms of decreased serum L-alanine aminotransferase activity and liver hydroxyproline content and improved liver histopathology, when compared with rats treated with verapamil or IFN-γ alone. Meanwhile, the area under the curve of verapamil increased significantly after single administration of verapamil and IFN-γ and the concentration of verapamil in plasma increased, but the metabolite : parent ratio of verapamil decreased after consecutive administrations of verapamil and IFN-γ. Furthermore, the activities of CYP3A in both the liver and the small intestine and the expression of Mdr in small intestine decreased in rats treated with verapamil and IFN-γ.
Conclusion: All these results indicated that the combination of verapamil and IFN-γ exerts a synergistic antifibrotic effect on rat liver fibrosis. The mechanism was partially based on the enhanced oral bioavailability of verapamil by increasing the intestinal absorption as well as reducing the first-pass metabolism, through inhibition of CYP3A activity and P-glycoprotein expression by IFN-γ.
aDepartment of Pharmacology, Basic Medical School of Wuhan University, Wuhan
bKey Laboratory of Allergy and Immunology, Hubei Province, China
cUMR CNRS-Université Henri Poincaré-Nancy ‘Physiopathologie et Pharmacologie Articulaires’, France
Correspondence to Professor Hui Wang, Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China
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Received 9 June 2009 Accepted 20 August 2009