Altering distribution profile of palbociclib by its prodrugs.

Autor: Järvinen J; School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland. Electronic address: Juulia.jarvinen@uef.fi., Montaser AB; School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland., Adla SK; School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland., Leppänen J; School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland., Lehtonen M; School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland., Vellonen KS; School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland., Laitinen T; School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland., Jalkanen A; School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland., Elmquist WF; Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN, United States., Timonen J; School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland; Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, P.O. Box 56, 00014 Helsinki, Finland., Huttunen KM; School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland., Rautio J; School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
Jazyk: angličtina
Zdroj: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2024 Jan 01; Vol. 192, pp. 106637. Date of Electronic Publication: 2023 Nov 13.
DOI: 10.1016/j.ejps.2023.106637
Abstrakt: Palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, is currently used clinically for treating hormone receptor-positive and human epidermal growth factor receptor 2 negative breast cancer. Additionally, it has the potential to be utilized in the treatment of various tumors, including malignant glioblastoma. Previous research has indicated that palbociclib is a substrate for two efflux transporters, P-glycoprotein (P-gp; MDR1) and breast cancer-resistant protein (BCRP), which restrict the brain exposure of palbociclib. In the present study, our objective was to alter the brain distribution pattern of palbociclib by creating and assessing two novel prodrugs through in vitro, in situ, and in vivo evaluations. To this end, we synthesized two prodrugs of palbociclib by attaching it to the tyrosine promoiety at the para- (PD1) and meta-(PD2) position via a carbamate bond. We hypothesized that the prodrugs could bypass efflux transporter-mediated drug resistance by leveraging the l-type amino acid transporter (LAT1) to facilitate their transport across the blood-brain barrier (BBB) and into cancer cells, such as glioma cells that express LAT1. The compounds PD1 and PD2 did not show selective binding and had limited inhibitory effects on LAT1 in three cell lines (MCF-7, U87-MG, HEK-hLAT1). However, PD1 and PD2 demonstrated the ability to evade efflux mechanisms, and their in vitro uptake profiles were comparable to that of palbociclib, indicating their potential for effective cellular transport. In in situ and in vivo studies, brain uptake was not significantly improved compared to palbociclib, but the pharmacokinetic profiles showed encouraging enhancements. PD1 exhibited a higher AUC brain/plasma ratio, suggesting safer dosing, while PD2 showed favorable long-acting pharmacokinetics. Although our prodrug design did not significantly improve palbociclib brain delivery due to the potential size limitation of the prodrugs, the study provides valuable insights for future prodrug development and drug delivery strategies targeting specific transporters.
Competing Interests: Declarations of Competing Interests None
(Copyright © 2023. Published by Elsevier B.V.)
Databáze: MEDLINE
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