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

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  • Author(s): Xu D;Xu D; Chen M; Guo Y; Liang G; Zhang B; Tan J; Magdalou J; Wang H
  • Source:
    European journal of gastroenterology & hepatology [Eur J Gastroenterol Hepatol] 2010 Apr; Vol. 22 (4), pp. 466-73.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Lippincott Williams And Wilkins Country of Publication: England NLM ID: 9000874 Publication Model: Print Cited Medium: Internet ISSN: 1473-5687 (Electronic) Linking ISSN: 0954691X NLM ISO Abbreviation: Eur J Gastroenterol Hepatol Subsets: MEDLINE
    • Publication Information:
      Publication: London : Lippincott Williams And Wilkins
      Original Publication: [London, UK ; Philadelphia, PA, USA] : Current Science, c1989-
    • Subject Terms:
      Antiviral Agents/*therapeutic use ; Calcium Channel Blockers/*therapeutic use ; Interferon-gamma/*therapeutic use ; Liver Cirrhosis, Experimental/*drug therapy ; Verapamil/*therapeutic use; Animals ; Antiviral Agents/pharmacokinetics ; Area Under Curve ; Biological Availability ; Calcium Channel Blockers/pharmacokinetics ; Cytochrome P-450 CYP3A/drug effects ; Drug Synergism ; Interferon-gamma/pharmacokinetics ; Liver Cirrhosis, Experimental/pathology ; Male ; Rats ; Rats, Wistar ; Treatment Outcome ; Verapamil/pharmacokinetics
    • Abstract:
      Objective: The objective of this study was to investigate the synergistic antifibrotic effect of verapamil and interferon-gamma (IFN-gamma) 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-gamma. 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-gamma 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-gamma alone. Meanwhile, the area under the curve of verapamil increased significantly after single administration of verapamil and IFN-gamma and the concentration of verapamil in plasma increased, but the metabolite : parent ratio of verapamil decreased after consecutive administrations of verapamil and IFN-gamma. 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-gamma.
      Conclusion: All these results indicated that the combination of verapamil and IFN-gamma 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-gamma
    • Accession Number:
      0 (Antiviral Agents)
      0 (Calcium Channel Blockers)
      82115-62-6 (Interferon-gamma)
      CJ0O37KU29 (Verapamil)
      EC 1.14.14.1 (Cytochrome P-450 CYP3A)
    • Publication Date:
      Date Created: 20100323 Date Completed: 20100708 Latest Revision: 20190907
    • Publication Date:
      20221213
    • Accession Number:
      10.1097/meg.0b013e32833226d5
    • Accession Number:
      20306567