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Antifibrotic Effects of Carvedilol and Impact of Liver Fibrosis on Carvedilol Pharmacokinetics in a Rat model

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Abstract

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.

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Authors and Affiliations

  1. Pharmacology and Toxicology Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt

    Ebtehal El-Demerdash

  2. Pharmacology and Toxicology Department, Faculty of Pharmacy, Misr International University, Cairo, Egypt

    Ebtehal El-Demerdash

  3. Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt

    Somaia A. Abdel-Sattar & Eman A. Mohamed

  4. Pharmacology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt

    Wesam M. El-Bakly

Authors
  1. Ebtehal El-Demerdash
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  2. Somaia A. Abdel-Sattar
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  3. Wesam M. El-Bakly
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  4. Eman A. Mohamed
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Corresponding author

Correspondence to Ebtehal El-Demerdash.

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Funding

No funding has been received for the conduct of this study.

Conflict of interest

All authors declare that they have no competing financial or personal interest or any kind of conflict of interest relevant to this study.

Ethical approval

All animal procedures were carried out in strict accordance with the internationally accepted principles for laboratory animal use and care. The study was approved by the Research Ethical Committee of the Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.

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El-Demerdash, E., Abdel-Sattar, S.A., El-Bakly, W.M. et al. Antifibrotic Effects of Carvedilol and Impact of Liver Fibrosis on Carvedilol Pharmacokinetics in a Rat model. Eur J Drug Metab Pharmacokinet 42, 767–779 (2017). https://doi.org/10.1007/s13318-016-0391-9

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  • DOI: https://doi.org/10.1007/s13318-016-0391-9

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