Cellular Uptake and Efflux of Palbociclib In Vitro in Single Cell and Spheroid Models

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

Research output: Contribution to journalArticle

Abstract

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 (C max 3.22 mM) and spheroids (C max 2.91 mM) were 32- and 29-fold higher and in DLD-1, 13- and 7-fold higher, respectively, than the media concentration (0.1 mM). 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. SIGNIFICANCE STATEMENT This study explores palbociclib uptake and efflux in single cell suspension and spheroid models of cancer. Large intracellular concentrations of palbociclib are found after drug exposure. The data from this study may aid understanding of the intratumoural pharmacokinetics of palbociclib, which is useful in understanding how drug distributes within tumor tissue and optimizing drug efficacy. Biomathematical modelling has the potential to derive intratumoural drug concentrations from plasma pharmacokinetics in patients.

LanguageEnglish
Pages242-251
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume370
Issue number2
Early online date12 Jun 2019
DOIs
Publication statusPublished - 1 Aug 2019

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Suspensions
Pharmaceutical Preparations
MCF-7 Cells
Neoplasms
Cyclin-Dependent Kinase 6
Theoretical Models
Pharmacokinetics
palbociclib
In Vitro Techniques
Cyclin-Dependent Kinase 4
Tandem Mass Spectrometry
Liquid Chromatography
Hormones
Breast Neoplasms
Cell Line
Therapeutics

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Jove, M., Spencer, J. A., Hubbard, M. E., Holden, E. C., O'dea, R. D., Brook, B. S., ... Twelves, C. J. (2019). Cellular Uptake and Efflux of Palbociclib In Vitro in Single Cell and Spheroid Models. Journal of Pharmacology and Experimental Therapeutics, 370(2), 242-251. https://doi.org/10.1124/jpet.119.256693
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. / Cellular Uptake and Efflux of Palbociclib In Vitro in Single Cell and Spheroid Models. In: Journal of Pharmacology and Experimental Therapeutics. 2019 ; Vol. 370, No. 2. pp. 242-251.
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Jove, M, Spencer, JA, Hubbard, ME, Holden, EC, O'dea, RD, Brook, BS, Phillips, RM, Smye, SW, Loadman, P & Twelves, CJ 2019, 'Cellular Uptake and Efflux of Palbociclib In Vitro in Single Cell and Spheroid Models', Journal of Pharmacology and Experimental Therapeutics, vol. 370, no. 2, pp. 242-251. https://doi.org/10.1124/jpet.119.256693

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.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 370, No. 2, 01.08.2019, p. 242-251.

Research output: Contribution to journalArticle

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AU - Brook, Bindi S

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