Article ; Online: Differential effects of dietary polyphenols on oral pharmacokinetics of cyclin-dependent kinase inhibitors in rats: a mechanistic framework for in vitro-in vivo extrapolation.
The Journal of pharmacy and pharmacology
2023 Volume 76, Issue 2, Page(s) 93–105
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 ...
| 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. |
|---|---|
| MeSH term(s) | Humans ; Rats ; Animals ; Cytochrome P-450 CYP3A/metabolism ; Caco-2 Cells ; Curcumin/pharmacology ; Quercetin/pharmacology ; Molecular Docking Simulation ; ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Administration, Oral ; Cyclin-Dependent Kinases/metabolism ; Aminopyridines ; Purines |
| Chemical Substances | ribociclib (TK8ERE8P56) ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; Curcumin (IT942ZTH98) ; Quercetin (9IKM0I5T1E) ; ATP Binding Cassette Transporter, Subfamily B, Member 1 ; Cyclin-Dependent Kinases (EC 2.7.11.22) ; Aminopyridines ; Purines |
| Language | English |
| Publishing date | 2023-12-12 |
| Publishing country | England |
| Document type | Journal Article |
| ZDB-ID | 3107-0 |
| ISSN | 2042-7158 ; 0022-3573 ; 0373-1022 |
| ISSN (online) | 2042-7158 |
| ISSN | 0022-3573 ; 0373-1022 |
| DOI | 10.1093/jpp/rgad115 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
| Uf I Zs.149: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG) |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.