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

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. I...

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Autores principales:	Karolina Gherbi, Stephen J. Briddon, Steven J. Charlton
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c6d4744a7ab4476ba13f01e717ce7624
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spelling	oai:doaj.org-article:c6d4744a7ab4476ba13f01e717ce76242021-12-02T11:40:35ZMicro-pharmacokinetics: Quantifying local drug concentration at live cell membranes10.1038/s41598-018-21100-x2045-2322https://doaj.org/article/c6d4744a7ab4476ba13f01e717ce76242018-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-21100-xhttps://doaj.org/toc/2045-2322Abstract 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 suggest that the true binding affinity of BY-propranolol for the β2-adrenoceptor is likely far lower than previously reported and highlights the critical importance of understanding the “micro-pharmacokinetic” profiles of ligands for membrane-associated proteins.Karolina GherbiStephen J. BriddonSteven J. CharltonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-8 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Karolina Gherbi Stephen J. Briddon Steven J. Charlton Micro-pharmacokinetics: Quantifying local drug concentration at live cell membranes
description	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 suggest that the true binding affinity of BY-propranolol for the β2-adrenoceptor is likely far lower than previously reported and highlights the critical importance of understanding the “micro-pharmacokinetic” profiles of ligands for membrane-associated proteins.
format	article
author	Karolina Gherbi Stephen J. Briddon Steven J. Charlton
author_facet	Karolina Gherbi Stephen J. Briddon Steven J. Charlton
author_sort	Karolina Gherbi
title	Micro-pharmacokinetics: Quantifying local drug concentration at live cell membranes
title_short	Micro-pharmacokinetics: Quantifying local drug concentration at live cell membranes
title_full	Micro-pharmacokinetics: Quantifying local drug concentration at live cell membranes
title_fullStr	Micro-pharmacokinetics: Quantifying local drug concentration at live cell membranes
title_full_unstemmed	Micro-pharmacokinetics: Quantifying local drug concentration at live cell membranes
title_sort	micro-pharmacokinetics: quantifying local drug concentration at live cell membranes
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/c6d4744a7ab4476ba13f01e717ce7624
work_keys_str_mv	AT karolinagherbi micropharmacokineticsquantifyinglocaldrugconcentrationatlivecellmembranes AT stephenjbriddon micropharmacokineticsquantifyinglocaldrugconcentrationatlivecellmembranes AT stevenjcharlton micropharmacokineticsquantifyinglocaldrugconcentrationatlivecellmembranes
_version_	1718395605420605440

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

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