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Synergistic antifibrotic effect of verapamil and interferon-γ in rats: partially based on enhanced verapamil oral bioavailability

Xu, Dana; Chen, Mana; Guo, Yua; Liang, Gaia; Zhang, Benjiana; Tan, Jingquanb; Magdalou, Jacquesc; Wang, Huia b

European Journal of Gastroenterology & Hepatology: April 2010 - Volume 22 - Issue 4 - p 466-473
doi: 10.1097/MEG.0b013e32833226d5
Original Articles: Liver Fibrosis and Cirrhosis

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

Tel: +86 27 687 58 665; fax: +86 27 873 316 70;

e-mail: clbwhcbd@yahoo.com

Received 9 June 2009 Accepted 20 August 2009

© 2010 Lippincott Williams & Wilkins, Inc.