Using Ex Vivo Porcine Jejunum to Identify Membrane Transporter Substrates: A Screening Tool for Early—Stage Drug Development
Robust, predictive ex vivo/in vitro models to study intestinal drug absorption by passive and active transport mechanisms are scarce. Membrane transporters can significantly impact drug uptake and transporter-mediated drug–drug interactions can play a pivotal role in determining the drug safety prof...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-09-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/8/9/340 |
| _version_ | 1797554072563220480 |
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| author | Yvonne E. Arnold Yogeshvar N. Kalia |
| author_facet | Yvonne E. Arnold Yogeshvar N. Kalia |
| author_sort | Yvonne E. Arnold |
| collection | DOAJ |
| description | Robust, predictive ex vivo/in vitro models to study intestinal drug absorption by passive and active transport mechanisms are scarce. Membrane transporters can significantly impact drug uptake and transporter-mediated drug–drug interactions can play a pivotal role in determining the drug safety profile. Here, the presence and activity of seven clinically relevant apical/basolateral drug transporters found in human jejunum were tested using ex vivo porcine intestine in a Ussing chamber system. Experiments using known substrates of peptide transporter 1 (PEPT1), organic anion transporting polypeptide (OATP2B1), organic cation transporter 1 (OCT1), P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multi drug resistance-associated protein 2 and 3 (MRP2 and MRP3), in the absence and presence of potent inhibitors, showed that there was a statistically significant change in apparent intestinal permeability <i>P<sub>app,pig</sub></i> (cm/s) in the presence of the corresponding inhibitor. For MRP2, a transporter reportedly present at relatively low concentration, although <i>P<sub>app,pig</sub></i> did not significantly change in the presence of the inhibitor, substrate deposition (<i>Q<sub>DEP</sub></i>) in the intestinal tissue was significantly increased. The activity of the seven transport proteins was successfully demonstrated and the results provided insight into their apical/basolateral localization. In conclusion, the results suggest that studies using the porcine intestine/Ussing chamber system, which could easily be integrated into the drug development process, might enable the early-stage identification of new molecular entities that are substrates of membrane transporters. |
| first_indexed | 2024-03-10T16:25:37Z |
| format | Article |
| id | doaj.art-93589500ce62477f96df80272a7e0faf |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T16:25:37Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-93589500ce62477f96df80272a7e0faf2023-11-20T13:15:08ZengMDPI AGBiomedicines2227-90592020-09-018934010.3390/biomedicines8090340Using Ex Vivo Porcine Jejunum to Identify Membrane Transporter Substrates: A Screening Tool for Early—Stage Drug DevelopmentYvonne E. Arnold0Yogeshvar N. Kalia1School of Pharmaceutical Sciences, University of Geneva, Centre Médical Universitaire, 1 rue Michel Servet, 1211 Geneva, SwitzerlandSchool of Pharmaceutical Sciences, University of Geneva, Centre Médical Universitaire, 1 rue Michel Servet, 1211 Geneva, SwitzerlandRobust, predictive ex vivo/in vitro models to study intestinal drug absorption by passive and active transport mechanisms are scarce. Membrane transporters can significantly impact drug uptake and transporter-mediated drug–drug interactions can play a pivotal role in determining the drug safety profile. Here, the presence and activity of seven clinically relevant apical/basolateral drug transporters found in human jejunum were tested using ex vivo porcine intestine in a Ussing chamber system. Experiments using known substrates of peptide transporter 1 (PEPT1), organic anion transporting polypeptide (OATP2B1), organic cation transporter 1 (OCT1), P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multi drug resistance-associated protein 2 and 3 (MRP2 and MRP3), in the absence and presence of potent inhibitors, showed that there was a statistically significant change in apparent intestinal permeability <i>P<sub>app,pig</sub></i> (cm/s) in the presence of the corresponding inhibitor. For MRP2, a transporter reportedly present at relatively low concentration, although <i>P<sub>app,pig</sub></i> did not significantly change in the presence of the inhibitor, substrate deposition (<i>Q<sub>DEP</sub></i>) in the intestinal tissue was significantly increased. The activity of the seven transport proteins was successfully demonstrated and the results provided insight into their apical/basolateral localization. In conclusion, the results suggest that studies using the porcine intestine/Ussing chamber system, which could easily be integrated into the drug development process, might enable the early-stage identification of new molecular entities that are substrates of membrane transporters.https://www.mdpi.com/2227-9059/8/9/340intestinal drug efflux/uptakeATP-binding cassette transportersolute carrier transporterex vivo porcine intestineUssing chamber |
| spellingShingle | Yvonne E. Arnold Yogeshvar N. Kalia Using Ex Vivo Porcine Jejunum to Identify Membrane Transporter Substrates: A Screening Tool for Early—Stage Drug Development Biomedicines intestinal drug efflux/uptake ATP-binding cassette transporter solute carrier transporter ex vivo porcine intestine Ussing chamber |
| title | Using Ex Vivo Porcine Jejunum to Identify Membrane Transporter Substrates: A Screening Tool for Early—Stage Drug Development |
| title_full | Using Ex Vivo Porcine Jejunum to Identify Membrane Transporter Substrates: A Screening Tool for Early—Stage Drug Development |
| title_fullStr | Using Ex Vivo Porcine Jejunum to Identify Membrane Transporter Substrates: A Screening Tool for Early—Stage Drug Development |
| title_full_unstemmed | Using Ex Vivo Porcine Jejunum to Identify Membrane Transporter Substrates: A Screening Tool for Early—Stage Drug Development |
| title_short | Using Ex Vivo Porcine Jejunum to Identify Membrane Transporter Substrates: A Screening Tool for Early—Stage Drug Development |
| title_sort | using ex vivo porcine jejunum to identify membrane transporter substrates a screening tool for early stage drug development |
| topic | intestinal drug efflux/uptake ATP-binding cassette transporter solute carrier transporter ex vivo porcine intestine Ussing chamber |
| url | https://www.mdpi.com/2227-9059/8/9/340 |
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