Drug Transport across Porcine Intestine Using an Ussing Chamber System: Regional Differences and the Effect of P-Glycoprotein and CYP3A4 Activity on Drug Absorption
Drug absorption across viable porcine intestines was investigated using an Ussing chamber system. The apparent permeability coefficients, <i>P<sub>app,pig</sub></i>, were compared to the permeability coefficients determined in humans in vivo, <i>P<sub>eff,human<...
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MDPI AG
2019-03-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/11/3/139 |
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| author | Yvonne E. Arnold Julien Thorens Stéphane Bernard Yogeshvar N. Kalia |
| author_facet | Yvonne E. Arnold Julien Thorens Stéphane Bernard Yogeshvar N. Kalia |
| author_sort | Yvonne E. Arnold |
| collection | DOAJ |
| description | Drug absorption across viable porcine intestines was investigated using an Ussing chamber system. The apparent permeability coefficients, <i>P<sub>app,pig</sub></i>, were compared to the permeability coefficients determined in humans in vivo, <i>P<sub>eff,human</sub></i>. Eleven drugs from the different Biopharmaceutical Classification System (BCS) categories absorbed by passive diffusion with published <i>P<sub>eff,human</sub></i> values were used to test the system. The initial experiments measured <i>P<sub>app,pig</sub></i> for each drug after application in a Krebs–Bicarbonate Ringer (KBR) buffer and in biorelevant media FaSSIF V2 and FeSSIF V2, mimicking fasted and fed states. Strong sigmoidal correlations were observed between <i>P<sub>eff,human</sub></i> and <i>P<sub>app,pig</sub></i>. Differences in the segmental <i>P<sub>app,pig</sub></i> of antipyrine, cimetidine and metoprolol confirmed the discrimination between drug uptake in the duodenum, jejunum and ileum (and colon); the results were in good agreement with human data in vivo. The presence of the P-gp inhibitor verapamil significantly increased <i>P<sub>app,pig</sub></i> across the ileum of the P-gp substrates cimetidine and ranitidine (<i>p</i> < 0.05). Clotrimazole, a potent CYP3A4 inhibitor, significantly increased <i>P<sub>app,pig</sub></i> of the CYP3A4 substrates midazolam, verapamil and tamoxifen and significantly decreased the formation of their main metabolites. In conclusion, the results showed that this is a robust technique to predict passive drug permeability under fasted and fed states, to identify regional differences in drug permeability and to demonstrate the activity of P-gp and CYP3A4. |
| first_indexed | 2024-04-11T10:58:46Z |
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| id | doaj.art-73077d596c4a4e9a8b3f936fe46cf56f |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-04-11T10:58:46Z |
| publishDate | 2019-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-73077d596c4a4e9a8b3f936fe46cf56f2022-12-22T04:28:41ZengMDPI AGPharmaceutics1999-49232019-03-0111313910.3390/pharmaceutics11030139pharmaceutics11030139Drug Transport across Porcine Intestine Using an Ussing Chamber System: Regional Differences and the Effect of P-Glycoprotein and CYP3A4 Activity on Drug AbsorptionYvonne E. Arnold0Julien Thorens1Stéphane Bernard2Yogeshvar N. Kalia3School of Pharmaceutical Sciences, University of Geneva & University of Lausanne, CMU-1 rue Michel Servet, 1211 Geneva 4, SwitzerlandDebiopharm International SA, Chemin Messidor 5-7, 1006 Lausanne, SwitzerlandDebiopharm International SA, Chemin Messidor 5-7, 1006 Lausanne, SwitzerlandSchool of Pharmaceutical Sciences, University of Geneva & University of Lausanne, CMU-1 rue Michel Servet, 1211 Geneva 4, SwitzerlandDrug absorption across viable porcine intestines was investigated using an Ussing chamber system. The apparent permeability coefficients, <i>P<sub>app,pig</sub></i>, were compared to the permeability coefficients determined in humans in vivo, <i>P<sub>eff,human</sub></i>. Eleven drugs from the different Biopharmaceutical Classification System (BCS) categories absorbed by passive diffusion with published <i>P<sub>eff,human</sub></i> values were used to test the system. The initial experiments measured <i>P<sub>app,pig</sub></i> for each drug after application in a Krebs–Bicarbonate Ringer (KBR) buffer and in biorelevant media FaSSIF V2 and FeSSIF V2, mimicking fasted and fed states. Strong sigmoidal correlations were observed between <i>P<sub>eff,human</sub></i> and <i>P<sub>app,pig</sub></i>. Differences in the segmental <i>P<sub>app,pig</sub></i> of antipyrine, cimetidine and metoprolol confirmed the discrimination between drug uptake in the duodenum, jejunum and ileum (and colon); the results were in good agreement with human data in vivo. The presence of the P-gp inhibitor verapamil significantly increased <i>P<sub>app,pig</sub></i> across the ileum of the P-gp substrates cimetidine and ranitidine (<i>p</i> < 0.05). Clotrimazole, a potent CYP3A4 inhibitor, significantly increased <i>P<sub>app,pig</sub></i> of the CYP3A4 substrates midazolam, verapamil and tamoxifen and significantly decreased the formation of their main metabolites. In conclusion, the results showed that this is a robust technique to predict passive drug permeability under fasted and fed states, to identify regional differences in drug permeability and to demonstrate the activity of P-gp and CYP3A4.https://www.mdpi.com/1999-4923/11/3/139intestinal permeabilityregional drug absorptionUssing chamberbiorelevant mediaP-gpCYP3A4 |
| spellingShingle | Yvonne E. Arnold Julien Thorens Stéphane Bernard Yogeshvar N. Kalia Drug Transport across Porcine Intestine Using an Ussing Chamber System: Regional Differences and the Effect of P-Glycoprotein and CYP3A4 Activity on Drug Absorption Pharmaceutics intestinal permeability regional drug absorption Ussing chamber biorelevant media P-gp CYP3A4 |
| title | Drug Transport across Porcine Intestine Using an Ussing Chamber System: Regional Differences and the Effect of P-Glycoprotein and CYP3A4 Activity on Drug Absorption |
| title_full | Drug Transport across Porcine Intestine Using an Ussing Chamber System: Regional Differences and the Effect of P-Glycoprotein and CYP3A4 Activity on Drug Absorption |
| title_fullStr | Drug Transport across Porcine Intestine Using an Ussing Chamber System: Regional Differences and the Effect of P-Glycoprotein and CYP3A4 Activity on Drug Absorption |
| title_full_unstemmed | Drug Transport across Porcine Intestine Using an Ussing Chamber System: Regional Differences and the Effect of P-Glycoprotein and CYP3A4 Activity on Drug Absorption |
| title_short | Drug Transport across Porcine Intestine Using an Ussing Chamber System: Regional Differences and the Effect of P-Glycoprotein and CYP3A4 Activity on Drug Absorption |
| title_sort | drug transport across porcine intestine using an ussing chamber system regional differences and the effect of p glycoprotein and cyp3a4 activity on drug absorption |
| topic | intestinal permeability regional drug absorption Ussing chamber biorelevant media P-gp CYP3A4 |
| url | https://www.mdpi.com/1999-4923/11/3/139 |
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