Pioglitazone and Ezetimibe combination improves Liver histopathology and biochemistry in experimental MASH models

Liver histopathology drug combination

Authors

  • Santosh Kumar Rai Mankind Research Centre, Mankind Pharma Ltd
  • Rakesh Kumar Mankind Research Centre, Mankind Pharma Limited
  • Amit Panwar Mankind Research Centre, Mankind Pharma Limited
  • Mohd Imran Khan Mankind Research Centre, Mankind Pharma Limited
  • Srinivasa Reddy B Mankind Research Centre, Mankind Pharma Limited
  • Bhavishya Vashist Mankind Research Centre, Mankind Pharma Limited
  • Rakesh Ishwar Patil Mankind Research Centre, Mankind Pharma Limited
  • Sazid Ali Mankind Research Centre, Mankind Pharma Limited
  • Anil Kumar Mankind Research Centre, Mankind Pharma Limited

DOI:

https://doi.org/10.62110/sciencein.cbl.2024.v11.677

Keywords:

MASLD, MASH, Pioglitazone, Ezetimibe, Drug combination, steatohepatitis , Liver histopathology

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are common clinico-pathological conditions that affecting over 30% of adults worldwide. Insulin resistance and hepatic lipid accumulation constitute the metabolic foundation of MASLD/MASH. Although previous studies have shown limited efficacy of activation of single PPARs (PPARα or PPARγ), ongoing clinical trials suggest that dual and pan-PPAR agonists may have a broader and more potent therapeutic effect on MASH by simultaneously targeting different inter-related mechanisms in this multisystem disease. Therefore, we hypothesized that a combination of PPARγ agonist (to enhance insulin sensitivity) with lipid lowering therapy (similar to PPARα) could have similar or better effects compared to PPARα/γ dual agonists. In the current study, we have investigated a novel combination of pioglitazone (a PPAR γ/α agonist) and ezetimibe (a cholesterol absorption inhibitor) in two different MASH animal models. We expected that anti-cholesterol absorption property of ezetimibe can augment the poor PPAR-α agonist property of pioglitazone in terms of lipid sensitivity in regulating steatosis. We tested pioglitazone at 2-3-fold reduced clinical dose (15mg/day) in combination to ezetimibe, since there are safety concerns associated with higher doses (30mg and 45mg, daily). Our results revealed that combination of low dose pioglitazone, with ezetimibe hold the ability to regulate the steatosis, hepatocyte inflammation and ballooning, which resulted in superior effects in terms of NAS as well as fibrosis score compared to pioglitazone alone (30mg/kg). Moreover, in vitro studies in human liver microsomes and mouse hepatocytes did not show any drug-drug interaction between pioglitazone and ezetimibe. Overall, this study provides a potential possibility for the clinical treatment of MASH with combination of pioglitazone and ezetimibe.

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Author Biographies

  • Santosh Kumar Rai, Mankind Research Centre, Mankind Pharma Ltd

    New Drug Discovery Research

  • Rakesh Kumar, Mankind Research Centre, Mankind Pharma Limited

    New Drug Discovery Research

  • Amit Panwar, Mankind Research Centre, Mankind Pharma Limited

     New Drug Discovery Research

  • Mohd Imran Khan, Mankind Research Centre, Mankind Pharma Limited

     New Drug Discovery Research

  • Srinivasa Reddy B, Mankind Research Centre, Mankind Pharma Limited

     New Drug Discovery Research

  • Bhavishya Vashist, Mankind Research Centre, Mankind Pharma Limited

     New Drug Discovery Research

  • Rakesh Ishwar Patil, Mankind Research Centre, Mankind Pharma Limited

     New Drug Discovery Research

  • Sazid Ali, Mankind Research Centre, Mankind Pharma Limited

     New Drug Discovery Research

  • Anil Kumar, Mankind Research Centre, Mankind Pharma Limited

     New Drug Discovery Research

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Published

2024-08-07

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Articles

URN

How to Cite

(1)
Rai, S. K.; Kumar, R.; Panwar, A. .; Khan, M. I. .; Reddy B, S. .; Vashist, B. .; Patil, R. I. .; Ali, S. .; Kumar, A. Pioglitazone and Ezetimibe Combination Improves Liver Histopathology and Biochemistry in Experimental MASH Models. Chem Biol Lett 2024, 11 (4), 677. https://doi.org/10.62110/sciencein.cbl.2024.v11.677.

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