Skip to main content

Research Repository

Advanced Search

Cellular uptake and efflux of palbociclib in vitro in single cell and spheroid models

Jove, Maria; Spencer, Jade A; Hubbard, Matthew E; Holden, Elizabeth C; O'Dea, Reuben D; Brook, Bindi S; Phillips, Roger M; Smye, Stephen W; Loadman, Paul; Twelves, Christopher J


Maria Jove

Jade A Spencer

Professor of Computational and Applied Mathematics

Elizabeth C Holden

Professor of Mathematical Medicine and Biology

Roger M Phillips

Stephen W Smye

Paul Loadman

Christopher J Twelves


Adequate drug distribution through tumors is essential for treatment to be effective. Palbociclib is a cyclin-dependent kinase 4/6 inhibitor approved for use in patients with hormone receptor positive, human epidermal growth factor receptor 2 negative metastatic breast cancer. It has unusual physicochemical properties, which may significantly influence its distribution in tumor tissue. We studied the penetration and distribution of palbociclib in vitro, including the use of multicellular three-dimensional models and mathematical modeling. MCF-7 and DLD-1 cell lines were grown as single cell suspensions (SCS) and spheroids; palbociclib uptake and efflux were studied using liquid chromatography-tandem mass spectrometry. Intracellular concentrations of palbociclib for MCF-7 SCS (Cmax 3.22 µM) and spheroids (Cmax 2.91 µM) were 32- and 29-fold higher and in DLD-1, 13- and 7-fold higher, respectively, than the media concentration (0.1 μM). Total palbociclib uptake was lower in DLD-1 cells than MCF-7 cells in both SCS and spheroids. Both uptake and efflux of palbociclib were slower in spheroids than SCS. These data were used to develop a mathematical model of palbociclib transport that quantifies key parameters determining drug penetration and distribution. The model reproduced qualitatively most features of the experimental data and distinguished between SCS and spheroids, providing additional support for hypotheses derived from the experimental data. Mathematical modeling has the potential for translating in vitro data into clinically relevant estimates of tumor drug concentrations.

Journal Article Type Article
Acceptance Date Jun 6, 2019
Online Publication Date Jun 12, 2019
Publication Date Aug 1, 2019
Deposit Date Jul 10, 2019
Journal Journal of Pharmacology and Experimental Therapeutics
Print ISSN 0022-3565
Electronic ISSN 1521-0103
Publisher American Society for Pharmacology and Experimental Therapeutics
Peer Reviewed Peer Reviewed
Volume 370
Issue 2
Article Number jpet.119.256693
Pages 242-251
Keywords Molecular Medicine; Pharmacology
Public URL
Publisher URL