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A Bidirectional Permeability Assay for beyond Rule of 5 Compounds

Bidirectional permeability measurement with cellular models grown on Transwell inserts is widely used in pharmaceutical research since it not only provides information about the passive permeability of a drug, but also about transport proteins involved in the active transport of drug substances acro...

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Autores principales: Cui, Yunhai, Desevaux, Cyril, Truebenbach, Ines, Sieger, Peter, Klinder, Klaus, Long, Alan, Sauer, Achim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400635/
https://www.ncbi.nlm.nih.gov/pubmed/34452112
http://dx.doi.org/10.3390/pharmaceutics13081146
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author Cui, Yunhai
Desevaux, Cyril
Truebenbach, Ines
Sieger, Peter
Klinder, Klaus
Long, Alan
Sauer, Achim
author_facet Cui, Yunhai
Desevaux, Cyril
Truebenbach, Ines
Sieger, Peter
Klinder, Klaus
Long, Alan
Sauer, Achim
author_sort Cui, Yunhai
collection PubMed
description Bidirectional permeability measurement with cellular models grown on Transwell inserts is widely used in pharmaceutical research since it not only provides information about the passive permeability of a drug, but also about transport proteins involved in the active transport of drug substances across physiological barriers. With the increasing number of investigative drugs coming from chemical space beyond Lipinski’s Rule of 5, it becomes more and more challenging to provide meaningful data with the standard permeability assay. This is exemplified here by the difficulties we encountered with the cyclic depsipeptides emodepside and its close analogs with molecular weight beyond 1000 daltons and cLogP beyond 5. The aim of this study is to identify potential reasons for these challenges and modify the permeability assays accordingly. With the modified assay, intrinsic permeability and in vitro efflux of depsipeptides could be measured reliably. The improved correlation to in vivo bioavailability and tissue distribution data indicated the usefulness of the modified permeability assay for the in vitro screening of compounds beyond the Rule of 5.
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spelling pubmed-84006352021-08-29 A Bidirectional Permeability Assay for beyond Rule of 5 Compounds Cui, Yunhai Desevaux, Cyril Truebenbach, Ines Sieger, Peter Klinder, Klaus Long, Alan Sauer, Achim Pharmaceutics Article Bidirectional permeability measurement with cellular models grown on Transwell inserts is widely used in pharmaceutical research since it not only provides information about the passive permeability of a drug, but also about transport proteins involved in the active transport of drug substances across physiological barriers. With the increasing number of investigative drugs coming from chemical space beyond Lipinski’s Rule of 5, it becomes more and more challenging to provide meaningful data with the standard permeability assay. This is exemplified here by the difficulties we encountered with the cyclic depsipeptides emodepside and its close analogs with molecular weight beyond 1000 daltons and cLogP beyond 5. The aim of this study is to identify potential reasons for these challenges and modify the permeability assays accordingly. With the modified assay, intrinsic permeability and in vitro efflux of depsipeptides could be measured reliably. The improved correlation to in vivo bioavailability and tissue distribution data indicated the usefulness of the modified permeability assay for the in vitro screening of compounds beyond the Rule of 5. MDPI 2021-07-27 /pmc/articles/PMC8400635/ /pubmed/34452112 http://dx.doi.org/10.3390/pharmaceutics13081146 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Cui, Yunhai
Desevaux, Cyril
Truebenbach, Ines
Sieger, Peter
Klinder, Klaus
Long, Alan
Sauer, Achim
A Bidirectional Permeability Assay for beyond Rule of 5 Compounds
title A Bidirectional Permeability Assay for beyond Rule of 5 Compounds
title_full A Bidirectional Permeability Assay for beyond Rule of 5 Compounds
title_fullStr A Bidirectional Permeability Assay for beyond Rule of 5 Compounds
title_full_unstemmed A Bidirectional Permeability Assay for beyond Rule of 5 Compounds
title_short A Bidirectional Permeability Assay for beyond Rule of 5 Compounds
title_sort bidirectional permeability assay for beyond rule of 5 compounds
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400635/
https://www.ncbi.nlm.nih.gov/pubmed/34452112
http://dx.doi.org/10.3390/pharmaceutics13081146
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