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A Cell-Free Approach Based on Phospholipid Characterization for Determination of the Cell Specific Unbound Drug Fraction (f(u,cell))
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0002-4533-7761
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
HBO Consult GmbH, D-04155 Leipzig, Germany.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0002-9094-2581
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2019 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 36, no 12, article id 178Article in journal (Refereed) Published
Abstract [en]

Purpose

The intracellular fraction of unbound compound (f(u,cell)) is an important parameter for accurate prediction of drug binding to intracellular targets. f(u,cell) is the result of a passive distribution process of drug molecules partitioning into cellular structures. Initial observations in our laboratory showed an up to 10-fold difference in the f(u,cell) of a given drug for different cell types. We hypothesized that these differences could be explained by the phospholipid (PL) composition of the cells, since the PL cell membrane is the major sink of unspecific drug binding. Therefore, we determined the f(u,cell) of 19 drugs in cell types of different origin.

Method

The cells were characterized for their total PL content and we used mass spectrometric PL profiling to delineate the impact of each of the four major cellular PL subspecies: phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylinositol (PI). The cell-based experiments were compared to cell-free experiments that used beads covered by PL bilayers consisting of the most abundant PL subspecies.

Results

PC was found to give the largest contribution to the drug binding. Improved correlations between the cell-based and cell-free assays were obtained when affinities to all four major PL subspecies were considered. Together, our data indicate that f(u,cell) is influenced by PL composition of cells.

Conclusion

We conclude that cellular PL composition varies between cell types and that cell-specific mixtures of PLs can replace cellular assays for determination of f(u,cell) as a rapid, small-scale assay covering a broad dynamic range.

Place, publisher, year, edition, pages
2019. Vol. 36, no 12, article id 178
Keywords [en]
cell-free assays, intracellular bioavailability, phospholipid membranes, unbound drug fraction
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-397951DOI: 10.1007/s11095-019-2717-1ISI: 000495617000001PubMedID: 31701258OAI: oai:DiVA.org:uu-397951DiVA, id: diva2:1382285
Funder
Swedish Research Council, 2822Swedish Research Council, 2017-01951EU, FP7, Seventh Framework Programme, 60751Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2020-01-02Bibliographically approved

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