Differential effects of dietary polyphenols on oral pharmacokinetics of cyclin-dependent kinase inhibitors in rats: a mechanistic framework for in vitro–in vivo extrapolation

Prajakta Harish Patil, Mrunal Pradeep Desai, Sumit Birangal, G. Gautham Shenoy, Jagadish Puralae Channabasavaiah

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1 Citation (Scopus)

Abstract

Objectives: Cyclin-dependent kinase inhibitors are subject to rapid first-pass metabolism, and their oral absorption is hindered by intestinal CYP3A4 and P-gp. The present study investigates the impact of dietary polyphenols on the oral pharmacokinetics of palbociclib and ribociclib, considering their potential as modulators of CYP3A4 and P-gp. Methods: Therefore, potential inhibitory effects of dietary polyphenols on drug metabolism and efflux of these drugs were investigated using molecular docking; in vitro preclinical assay using rat liver microsomes and Caco-2 cell monolayers; in vivo, pharmacokinetic parameters were determined in rats pretreated with dietary polyphenols. Key findings: Curcumin and quercetin have the highest binding affinities to the PXR’s AF-2 region cluster. Curcumin and quercetin significantly inhibited both intestinal efflux and CYP3A4-mediated metabolism of palbociclib and ribociclib (P < .05). In rats pretreated with curcumin, Cmax of palbociclib exhibited a 5.13% increase, while the AUC0-24h of ribociclib showed a significant increase of 18.83% (P < .05). Quercetin administration, notably, impedes the pharmacokinetics of palbociclib. However, the pharmacokinetics of ribociclib remains unaffected by quercetin. Conclusions: In conclusion, the utilization of curcumin as a bioenhancer can enhance the bioavailability of dual substrates of P-gp and CYP3A4.

Original languageEnglish
Pages (from-to)93-105
Number of pages13
JournalJournal of Pharmacy and Pharmacology
Volume76
Issue number2
DOIs
Publication statusPublished - 01-02-2024

All Science Journal Classification (ASJC) codes

  • General Medicine

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