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Volume 32, Issue 4
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X

Abstract

Introduction

P-glycoprotein, an ATP-dependent efflux transporter, plays a crucial role in eliminating cellular toxins and affects the intracellular concentration and bioavailability of CDK 4/6 inhibitors. Moreover, dietary flavonoids are natural bio-enhancers that can effectively inhibit the efflux function of these transporters. Therefore, this study aimed to assess the impact of dietary polyphenols on the inhibition of P-glycoprotein and the subsequent efflux of CDK inhibitors palbociclib and ribociclib.

Methods

A molecular docking approach was implemented to evaluate the binding interaction characteristics of CDK4/6 inhibitors in the presence of dietary polyphenols at the ATP binding site. Furthermore, the stability of the complexes was evaluated in two conformations of P-glycoprotein, followed by an everted gut sac experiment.

Results

The findings demonstrated that the binding of curcumin and quercetin with high affinity (-51.63 and -47.16 Kcal/mol) to ATP binding sites of P-glycoprotein-palbociclib and ribociclib inward conformation complexes resulted in good stability of complex and minimal fluctuation throughout the course of the simulation. It was evident from the everted gut sac study that the presence of 100 µM of curcumin resulted in an increase of 1.77 and 4.20-fold in the intestinal transit of palbociclib and ribociclib, respectively.

Conclusion

The study emphasizes the significance of curcumin and quercetin as inhibitors of P-glycoprotein, demonstrating their potential to decrease the efflux of palbociclib and ribociclib, consequently contributing to their bioavailability enhancement.

© 2025 Bentham Science Publishers
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2024-09-12
2025-04-09

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A Molecular Dynamic Simulation, Structural Analysis, and Ex Vivo Insights into the P-glycoprotein Mediated Interactions of Dietary Polyphenols with Cyclin-dependent Kinase Inhibitors: A Potential Strategy to Counteract Drug Efflux
Curr. Med. Chem. 32, 788 (2025); https://doi.org/10.2174/0109298673319832240829164046
/content/journals/cmc/10.2174/0109298673319832240829164046
/content/journals/cmc/10.2174/0109298673319832240829164046
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  • Article Type:     Research Article
Keyword(s): ATP; curcumin; Cyclin-dependent kinase inhibitors; dietary polyphenols; multidrug resistance; p-glycoprotein inhibition; quercetin

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