Micro-pharmacokinetics: Quantifying local drug concentration at live cell membranes

Scientific Reports
Karolina GherbiSteven J Charlton

Abstract

Fundamental equations for determining pharmacological parameters, such as the binding affinity of a ligand for its target receptor, assume a homogeneous distribution of ligand, with concentrations in the immediate vicinity of the receptor being the same as those in the bulk aqueous phase. It is, however, known that drugs are able to interact directly with the plasma membrane, potentially increasing local ligand concentrations around the receptor. We have previously reported an influence of ligand-phospholipid interactions on ligand binding kinetics at the β2-adrenoceptor, which resulted in distinct "micro-pharmacokinetic" ligand profiles. Here, we directly quantified the local concentration of BODIPY630/650-PEG8-S-propranolol (BY-propranolol), a fluorescent derivative of the classical β-blocker propranolol, at various distances above membranes of single living cells using fluorescence correlation spectroscopy. We show for the first time a significantly increased ligand concentration immediately adjacent to the cell membrane compared to the bulk aqueous phase. We further show a clear role of both the cell membrane and the β2-adrenoceptor in determining high local BY-propranolol concentrations at the cell surface. These data sugg...Continue Reading

References

Mar 1, 1994·The European Respiratory Journal·G P AndersonK F Rabe
Sep 5, 2001·The Journal of Biological Chemistry·R S OstromP A Insel
Feb 4, 2003·Journal of Lipid Research·Linda J Pike
Nov 20, 2003·Chemistry and Physics of Lipids·P ZoumpoulakisT Mavromoustakos
Apr 9, 2004·Proceedings of the National Academy of Sciences of the United States of America·S J BriddonS J Hill
May 19, 2004·Biochemistry·Oliver HegenerHanns Häberlein
Aug 12, 2008·Biochimica Et Biophysica Acta·Stephen J BriddonFrancisco Ciruela
Nov 6, 2008·Cell·Jean B RegardShaun R Coughlin
Aug 4, 2009·Molecular and Cellular Endocrinology·G Vauquelin, A Packeu
Jan 29, 2010·British Journal of Pharmacology·Jillian G BakerStephen J Hill
Oct 1, 2010·British Journal of Pharmacology·Georges Vauquelin, Steven J Charlton
May 17, 2011·The Journal of Physiological Sciences : JPS·Eri H HayakawaYuichi Takakuwa
Feb 22, 2012·Science·Michael A HansonRaymond C Stevens
Jan 8, 2013·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Catarina Pereira-LeiteSalette Reis
Apr 1, 2014·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Gesche FörstMartin Hof
Apr 22, 2015·PloS One·Damaris Bausch-FluckBernd Wollscheid
Dec 19, 2015·Nature Reviews. Drug Discovery·Robert A Copeland
May 11, 2016·Biochimica Et Biophysica Acta·Christopher G MayneEmad Tajkhorshid

❮ Previous
Next ❯

Citations

Sep 10, 2019·British Journal of Pharmacology·Rob HillGraeme Henderson
Mar 27, 2020·Annual Review of Biochemistry·M B RobersK V Wood
Feb 26, 2019·British Journal of Pharmacology·Srgjan Civciristov, Michelle L Halls
Nov 13, 2020·Frontiers in Cell and Developmental Biology·Michael A KalwatMelanie H Cobb
May 25, 2021·British Journal of Pharmacology·Eamonn KellyGraeme Henderson
Jul 15, 2021·Nature Reviews. Drug Discovery·Jian Payandeh, Matthew Volgraf
Sep 10, 2020·Journal of the American Chemical Society·Roman C SarottErick M Carreira
Aug 3, 2021·Molecular Pharmacology·Christopher T SzlenkSenthil Natesan
Nov 30, 2021·Journal of Chemical Information and Modeling·Callum J DicksonJose S Duca

❮ Previous
Next ❯

Methods Mentioned

BETA
fluorescence correlation spectroscopy
FCS
saturation binding
Fluorescence

Software Mentioned

Zen2010
Prism
Zeiss AIM
Graphpad Prism
GraphPad

Related Concepts

Related Feeds

Adrenergic Receptors: Trafficking

Adrenergic receptor trafficking is an active physiological process where adrenergic receptors are relocated from one region of the cell to another or from one type of cell to another. Discover the latest research on adrenergic receptor trafficking here.