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

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    Publication date
    2019-08-01
    Author
    Jove, M.
    Spencer, Jade A.
    Hubbard, M.E.
    Holden, E.C.
    O'Dea, R.D.
    Brook, B.S.
    Phillips, Roger M.
    Smye, S.W.
    Loadman, Paul M.
    Twelves, C.J.
    Keyword
    Cancer
    Drug efflux
    Mass spectrometry
    Mathematical modeling
    Pharmacokinetic/pharmacodynamic modeling
    Peer-Reviewed
    Yes
    
    Metadata
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    Abstract
    Adequate drug distribution through tumours is essential for treatment to be effective. Palbociclib is a cyclin-dependent kinase (CDK) 4/6 inhibitor approved for use in patients with hormone receptor (HR) positive, HER2 negative metastatic breast cancer (BC). It has unusual physicochemical properties, which may significantly influence its distribution in tumour tissue. We studied the penetration and distribution of palbociclib in vitro, including the use of multicellular three-dimensional models and mathematical modelling. 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 (LC-MS/MS). 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 both in SCS and in 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 modelling has the potential for translating in vitro data into clinically relevant estimates of tumour drug concentrations.
    URI
    http://hdl.handle.net/10454/17174
    Version
    Accepted manuscript
    Citation
    Jove M, Spencer JA, Hubbard ME et al (2019) Cellular uptake and efflux of palbociclib in vitro in single cell and spheroid models. The Journal of Pharmacology and Experimental Therapeutics. 370(2): 242-251.
    Link to publisher’s version
    https://doi.org/10.1124/jpet.119.256693
    Type
    Article
    Collections
    Life Sciences Publications

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