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

帕博西利布 球体 体外 化学 流出 细胞内 分布(数学) 生物物理学 药理学 生物 癌症 乳腺癌 生物化学 内科学 医学 转移性乳腺癌 数学 数学分析
作者
Maria Jové,John Spencer,M.E. Hubbard,E Holden,Reuben D. O’Dea,Bindi S. Brook,Roger M. Phillips,S W Smye,Paul M. Loadman,Chris Twelves
出处
期刊:Journal of Pharmacology and Experimental Therapeutics [American Society for Pharmacology & Experimental Therapeutics]
卷期号:370 (2): 242-251 被引量:10
标识
DOI:10.1124/jpet.119.256693
摘要

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.

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.
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