Title:Molecular Insights into the Mechanism of Modulatory Effects of Proton Pump Inhibitors
on P-glycoprotein Mediated Drug Transport of Palbociclib and Ribociclib
Volume: 24
Issue: 6
Author(s): Mrunal Pradeep Desai, Prajakta Harish Patil, Sai Krishna Anand Vullendula, Sumit Birangal, G. Gautham Shenoy, Mahadev Rao, Swapnil Jayant Dengale, Krishnamurthy Bhat and Jagadish Puralae Channabasavaiah*
Affiliation:
- Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education,
Manipal, Karnataka, 576104, India
Keywords:
Cyclin-dependent kinase inhibitors, Drug-drug interaction, Everted gut-sac, Molecular docking, P-glycoprotein, Proton pump inhibitors.
Abstract:
Background: Palbociclib and ribociclib are substrates of efflux transporter P-glycoprotein which plays a
key role in absorption and transport of these drugs. Proton pump inhibitors, when co-administered with them are
known to show inhibitory effect on P-glycoprotein.
Objective: Therefore, this study aims to investigate the role of proton pump inhibitors in inhibition of P-glycoprotein
mediated efflux of palbociclib and ribociclib.
Method: A combined approach of molecular docking and ex vivo everted gut sac model was implemented to predict
the potential of proton pump inhibitors i.e., omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole to
inhibit the P-glycoprotein mediated intestinal transport of palbociclib and ribociclib and study the molecular basis of
interaction taking place.
Results: Molecular docking studies revealed that omeprazole, rabeprazole and pantoprazole bound to the ATP site of
nucleotide binding domain with binding energies of -27.53, -29.56 and -38.44 Kcal/mol respectively. In ex vivo
studies, rabeprazole and omeprazole, affected the absorptive permeability of palbociclib by 3.04 and 1.26 and
ribociclib by 1.76 and 2.54 folds, respectively. Results of molecular docking studies and ex vivo studies highlighted
that proton pump inhibitors bound to the ATP binding site to block its hydrolysis thereby inhibiting the
P-glycoprotein mediated efflux of palbociclib and ribociclib.
Conclusion: The experimental evidence presented highlights the fact that proton pump inhibitors have potential to
inhibit P-glycoprotein, giving rise to drug interactions with palbociclib and ribociclib. Hence, monitoring is required
while proton pump inhibitors and cyclin-dependent kinase inhibitors are being co-administered to avoid adverse
events.
