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Predicting Oral Absorption for Compounds Outside the Rule of Five Property Space

Huth, Felix, Domange, Norbert, Poller, Birk, Vapurcuyan, Natasha, Durrwell, Alexandre, Hanna, Imad and Faller, Bernard (2021) Predicting Oral Absorption for Compounds Outside the Rule of Five Property Space. Journal of pharmaceutical sciences, 110 (6). pp. 2562-2569. ISSN 00223549


The estimation of the extent of absorption of drug candidates intended for oral drug delivery is an
important selection criteria in drug discovery. The use of cell-based transwell assays examining flux
across cell-monolayers (e.g., Caco-2 or MDCK cells) usually provide satisfactory predictions of the extent
of absorption in vivo. These predictions often fall short of expection for molecules outside the traditional
low molecular weight property space. In this manuscript the transwell permeability assay was modified
to circumvent potential issues that can be encountered when evaluating the aforementioned drug
molecules. Particularly, the addition of albumin in the acceptor compartment to reduce potential binding
to cells and the acceptor compartment, improved the predictive power of the assay. Cellular binding and
lysosomal trapping effects are significantly reduced for larger molecules, particularly lipophilic bases
under these more physiological conditions, resulting in higher recovery values and a better prediction
power. The data indicate that lysosomal trapping does not impact the rate of absorption of lipophilic
bases in general but is rather an exception. Finally, compounds believed to permeate by passive mechanisms
were used in a calibration curve for the effective prediction of the fraction absorbed of molecules
of interest in current medicinal chemistry efforts.

Item Type: Article
Keywords: Permeability, MDCK, fraction absorbed, lipophilic compounds, BSA, lysosomal trapping, MDR1 knockout
Date Deposited: 17 Jun 2021 00:45
Last Modified: 17 Jun 2021 00:45


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