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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| Veröffentlicht in: | Pharmaceutics 2021-07, Vol.13 (8), p.1146, Article 1146 |
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| creator | Cui, Yunhai Desevaux, Cyril Truebenbach, Ines Sieger, Peter Klinder, Klaus Long, Alan Sauer, Achim |
| 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. |
| doi_str_mv | 10.3390/pharmaceutics13081146 |
| format | Article |
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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/). 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| subjects | Binding sites Brain research Drug dosages drug transporter efflux Equilibrium Life Sciences & Biomedicine Lipinski’s Rule of 5 oral bioavailability Permeability Pharmaceutical industry Pharmacology & Pharmacy physiological barrier Physiology Plasma Polyvinyl alcohol Proteins R&D Research & development Retention Science & Technology |
| title | A Bidirectional Permeability Assay for beyond Rule of 5 Compounds |
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