Molecular Insights into the Mechanism of Modulatory Effects of Proton Pump Inhibitors on P-glycoprotein Mediated Drug Transport of Palbociclib and Ribociclib

Abstract

Background: Palbociclib and ribociclib are substrates of efflux transporter, P-glycoprotein 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.

The Association between Proton Pump Inhibitors and the Effectiveness of CDK Inhibitors in HR+/HER- Advanced Breast Cancer Patients: A Systematic Review and Meta-Analysis

“…Palbociclib and Ribociclib act as substrates for the efflux transporter P-glycoprotein (Pgp), and, as a matter of fact, PPIs are known as moderate inhibitors of P-gp [34]. In ex vivo studies, it was found that rabeprazole and omeprazole decreased the absorptive permeability of Palbociclib by 3.04-and 1.26-fold, respectively, and of Ribociclib by 1.76and 2.54-fold, respectively, highlighting the ability of PPIs to inhibit the P-gp-mediated efflux of both CDKIs [35]. Although the PPI inhibition of CDKI efflux could theoretically increase the concentration of a CDKI, thereby increasing drug toxicity, our meta-analysis demonstrated that there was no difference in dose reduction due to drug toxicity between PPI users and non-users.…”