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Rapid measurement of intracellular unbound drug concentrations.

Abstract：

:Intracellular unbound drug concentrations determine affinity to targets in the cell interior. However, due to difficulties in measuring them, they are often overlooked in pharmacology. Here we present a simple experimental technique for the determination of unbound intracellular drug concentrations in cultured cells that is based on parallel measurements of cellular drug binding and steady-state intracellular drug concentrations. Binding in HEK293 cells was highly correlated with binding in liver-derived systems, whereas binding in plasma did not compare well with cellular binding. Compound lipophilicity increased drug binding, while negative charge and aromatic functional groups decreased binding. Intracellular accumulation of unbound drug was consistent with pH-dependent subcellular sequestration, as confirmed by modeling and by inhibition of subcellular pH gradients. The approach developed here can be used to measure intracellular unbound drug concentrations in more complex systems, for example, cell lines with controlled expression of transporters and enzymes or primary cells.

journal_name

Mol Pharm

journal_title

Molecular pharmaceutics

authors

Mateus A,Matsson P,Artursson P

doi

10.1021/mp4000822

subject

Has Abstract

pub_date

2013-06-03 00:00:00

pages

2467-78

issue

6

eissn

1543-8384

issn

1543-8392

journal_volume

10

pub_type

杂志文章

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