Mucin-Protected Caco-2 Assay to Study Drug Permeation in the Presence of Complex Biorelevant Media
The poor solubility and permeability of compounds beyond Lipinski’s Rule of Five (bRo5) are major challenges for cell-based permeability assays. Due to their incompatibility with gastrointestinal components in biorelevant media, the exploration of important questions addressing food effects is limit...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-03-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/4/699 |
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| author | Dong Ye Álvaro López Mármol Verena Lenz Patricia Muschong Anita Wilhelm-Alkubaisi Manuel Weinheimer Mirko Koziolek Kerstin A. Sauer Loic Laplanche Mario Mezler |
| author_facet | Dong Ye Álvaro López Mármol Verena Lenz Patricia Muschong Anita Wilhelm-Alkubaisi Manuel Weinheimer Mirko Koziolek Kerstin A. Sauer Loic Laplanche Mario Mezler |
| author_sort | Dong Ye |
| collection | DOAJ |
| description | The poor solubility and permeability of compounds beyond Lipinski’s Rule of Five (bRo5) are major challenges for cell-based permeability assays. Due to their incompatibility with gastrointestinal components in biorelevant media, the exploration of important questions addressing food effects is limited. Thus, we established a robust mucin-protected Caco-2 assay to allow the assessment of drug permeation in complex biorelevant media. To do that, the assay conditions were first optimized with dependence of the concentration of porcine mucin added to the cells. Mucin-specific effects on drug permeability were evaluated by analyzing cell permeability values for 15 reference drugs (BCS class I–IV). Secondly, a sigmoidal relationship between mucin-dependent permeability and fraction absorbed in human (<i>f</i><sub>a</sub>) was established. A case study with venetoclax (BCS class IV) was performed to investigate the impact of medium complexity and the prandial state on drug permeation. Luminal fluids obtained from the tiny-TIM system showed a higher solubilization capacity for venetoclax, and a better read-out for the drug permeability, as compared to FaSSIF or FeSSIF media. In conclusion, the mucin-protected Caco-2 assay combined with biorelevant media improves the mechanistic understanding of drug permeation and addresses complex biopharmaceutical questions, such as food effects on oral drug absorption. |
| first_indexed | 2024-03-09T10:30:11Z |
| format | Article |
| id | doaj.art-735fe606651748828518a48a13532d69 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T10:30:11Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-735fe606651748828518a48a13532d692023-12-01T21:18:25ZengMDPI AGPharmaceutics1999-49232022-03-0114469910.3390/pharmaceutics14040699Mucin-Protected Caco-2 Assay to Study Drug Permeation in the Presence of Complex Biorelevant MediaDong Ye0Álvaro López Mármol1Verena Lenz2Patricia Muschong3Anita Wilhelm-Alkubaisi4Manuel Weinheimer5Mirko Koziolek6Kerstin A. Sauer7Loic Laplanche8Mario Mezler9Drug Metabolism and Pharmacokinetics—Bioanalytical Research, AbbVie Deutschland GmbH & Co. KG, 67061 Ludwigshafen, GermanyNCE Formulation Sciences, AbbVie Deutschland GmbH & Co. KG, 67061 Ludwigshafen, GermanyNCE Formulation Sciences, AbbVie Deutschland GmbH & Co. KG, 67061 Ludwigshafen, GermanyDrug Metabolism and Pharmacokinetics—Bioanalytical Research, AbbVie Deutschland GmbH & Co. KG, 67061 Ludwigshafen, GermanyDrug Metabolism and Pharmacokinetics—Bioanalytical Research, AbbVie Deutschland GmbH & Co. KG, 67061 Ludwigshafen, GermanyDrug Metabolism and Pharmacokinetics—Bioanalytical Research, AbbVie Deutschland GmbH & Co. KG, 67061 Ludwigshafen, GermanyNCE Formulation Sciences, AbbVie Deutschland GmbH & Co. KG, 67061 Ludwigshafen, GermanyNCE Formulation Sciences, AbbVie Deutschland GmbH & Co. KG, 67061 Ludwigshafen, GermanyDrug Metabolism and Pharmacokinetics—Bioanalytical Research, AbbVie Deutschland GmbH & Co. KG, 67061 Ludwigshafen, GermanyDrug Metabolism and Pharmacokinetics—Bioanalytical Research, AbbVie Deutschland GmbH & Co. KG, 67061 Ludwigshafen, GermanyThe poor solubility and permeability of compounds beyond Lipinski’s Rule of Five (bRo5) are major challenges for cell-based permeability assays. Due to their incompatibility with gastrointestinal components in biorelevant media, the exploration of important questions addressing food effects is limited. Thus, we established a robust mucin-protected Caco-2 assay to allow the assessment of drug permeation in complex biorelevant media. To do that, the assay conditions were first optimized with dependence of the concentration of porcine mucin added to the cells. Mucin-specific effects on drug permeability were evaluated by analyzing cell permeability values for 15 reference drugs (BCS class I–IV). Secondly, a sigmoidal relationship between mucin-dependent permeability and fraction absorbed in human (<i>f</i><sub>a</sub>) was established. A case study with venetoclax (BCS class IV) was performed to investigate the impact of medium complexity and the prandial state on drug permeation. Luminal fluids obtained from the tiny-TIM system showed a higher solubilization capacity for venetoclax, and a better read-out for the drug permeability, as compared to FaSSIF or FeSSIF media. In conclusion, the mucin-protected Caco-2 assay combined with biorelevant media improves the mechanistic understanding of drug permeation and addresses complex biopharmaceutical questions, such as food effects on oral drug absorption.https://www.mdpi.com/1999-4923/14/4/699permeationCaco-2 cellsdrug absorptionbiorelevant mediabioavailabilityoral drug delivery |
| spellingShingle | Dong Ye Álvaro López Mármol Verena Lenz Patricia Muschong Anita Wilhelm-Alkubaisi Manuel Weinheimer Mirko Koziolek Kerstin A. Sauer Loic Laplanche Mario Mezler Mucin-Protected Caco-2 Assay to Study Drug Permeation in the Presence of Complex Biorelevant Media Pharmaceutics permeation Caco-2 cells drug absorption biorelevant media bioavailability oral drug delivery |
| title | Mucin-Protected Caco-2 Assay to Study Drug Permeation in the Presence of Complex Biorelevant Media |
| title_full | Mucin-Protected Caco-2 Assay to Study Drug Permeation in the Presence of Complex Biorelevant Media |
| title_fullStr | Mucin-Protected Caco-2 Assay to Study Drug Permeation in the Presence of Complex Biorelevant Media |
| title_full_unstemmed | Mucin-Protected Caco-2 Assay to Study Drug Permeation in the Presence of Complex Biorelevant Media |
| title_short | Mucin-Protected Caco-2 Assay to Study Drug Permeation in the Presence of Complex Biorelevant Media |
| title_sort | mucin protected caco 2 assay to study drug permeation in the presence of complex biorelevant media |
| topic | permeation Caco-2 cells drug absorption biorelevant media bioavailability oral drug delivery |
| url | https://www.mdpi.com/1999-4923/14/4/699 |
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