Proximal tubule-on-chip as a model for predicting cation transport and drug transporter dynamics
Abstract Deciphering the sources of variability in drug responses requires to understand the processes modulating drug pharmacokinetics. However, pharmacological research suffers from poor reproducibility across clinical, animal, and experimental models. Predictivity can be improved by using Organs-...
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Nature Portfolio
2025-01-01
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| Online Access: | https://doi.org/10.1038/s41598-025-85653-4 |
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| author | Isy Petit Quentin Faucher Jean-Sébastien Bernard Perrine Giunchi Antoine Humeau François-Ludovic Sauvage Pierre Marquet Nicolas Védrenne Florent Di Meo |
| author_facet | Isy Petit Quentin Faucher Jean-Sébastien Bernard Perrine Giunchi Antoine Humeau François-Ludovic Sauvage Pierre Marquet Nicolas Védrenne Florent Di Meo |
| author_sort | Isy Petit |
| collection | DOAJ |
| description | Abstract Deciphering the sources of variability in drug responses requires to understand the processes modulating drug pharmacokinetics. However, pharmacological research suffers from poor reproducibility across clinical, animal, and experimental models. Predictivity can be improved by using Organs-on-Chips, which are more physiological, human-oriented, micro-engineered devices that include microfluidics. OoC are particularly relevant at the fundamental and preclinical stages of drug development by providing more accurate assessment of key pharmacokinetic events. We have developed a proximal tubule-on-a-chip model combining commercial microfluidic and chip technologies. Using the RPTEC/TERT1 cell line, we set up a dual-flow system with antiparallel flows to mimic the dynamics of blood and urine. We assessed transporters mRNA expression, cellular polarization and protein expression via immunofluorescence, and monitored the transcellular transport of prototypic xenobiotics by determining their efflux ratios. Our results show that flow exposure significantly modulate mRNA expression of drug membrane transporters. Dynamic conditions also enhance cell polarization, as evidenced by preferential basal and apical expressions of Na + /K + -ATPase, P-gp, OCT2, and MATE1 , as well as the cellular secretory profile. We demonstrated unidirectional transcellular transport of metformin with a higher efflux than influx ratio, inhibited with OCT2 inhibitor, thus confirming the relevance of our proximal tubule-on-a-chip set up for cation transport investigations. Our proximal tubule-on-a-chip can also be used to explore the interactions between transporters, xenobiotics, and endogenous metabolites, possibly involved in the variability of individual drug responses. This study provides additional evidence that OoC can help bridge the gaps between systemic and local pharmacokinetics. |
| format | Article |
| id | doaj-art-cfdf4b852a454451b8699495f37a24ff |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-cfdf4b852a454451b8699495f37a24ff2025-01-26T12:32:44ZengNature PortfolioScientific Reports2045-23222025-01-0115111210.1038/s41598-025-85653-4Proximal tubule-on-chip as a model for predicting cation transport and drug transporter dynamicsIsy Petit0Quentin Faucher1Jean-Sébastien Bernard2Perrine Giunchi3Antoine Humeau4François-Ludovic Sauvage5Pierre Marquet6Nicolas Védrenne7Florent Di Meo8U1248 Pharmacology & Transplantation, Inserm, Univ. LimogesDivision of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht UniversityU1248 Pharmacology & Transplantation, Inserm, Univ. LimogesU1248 Pharmacology & Transplantation, Inserm, Univ. LimogesU1248 Pharmacology & Transplantation, Inserm, Univ. LimogesU1248 Pharmacology & Transplantation, Inserm, Univ. LimogesU1248 Pharmacology & Transplantation, Inserm, Univ. LimogesU1248 Pharmacology & Transplantation, Inserm, Univ. LimogesU1248 Pharmacology & Transplantation, Inserm, Univ. LimogesAbstract Deciphering the sources of variability in drug responses requires to understand the processes modulating drug pharmacokinetics. However, pharmacological research suffers from poor reproducibility across clinical, animal, and experimental models. Predictivity can be improved by using Organs-on-Chips, which are more physiological, human-oriented, micro-engineered devices that include microfluidics. OoC are particularly relevant at the fundamental and preclinical stages of drug development by providing more accurate assessment of key pharmacokinetic events. We have developed a proximal tubule-on-a-chip model combining commercial microfluidic and chip technologies. Using the RPTEC/TERT1 cell line, we set up a dual-flow system with antiparallel flows to mimic the dynamics of blood and urine. We assessed transporters mRNA expression, cellular polarization and protein expression via immunofluorescence, and monitored the transcellular transport of prototypic xenobiotics by determining their efflux ratios. Our results show that flow exposure significantly modulate mRNA expression of drug membrane transporters. Dynamic conditions also enhance cell polarization, as evidenced by preferential basal and apical expressions of Na + /K + -ATPase, P-gp, OCT2, and MATE1 , as well as the cellular secretory profile. We demonstrated unidirectional transcellular transport of metformin with a higher efflux than influx ratio, inhibited with OCT2 inhibitor, thus confirming the relevance of our proximal tubule-on-a-chip set up for cation transport investigations. Our proximal tubule-on-a-chip can also be used to explore the interactions between transporters, xenobiotics, and endogenous metabolites, possibly involved in the variability of individual drug responses. This study provides additional evidence that OoC can help bridge the gaps between systemic and local pharmacokinetics.https://doi.org/10.1038/s41598-025-85653-4Organ-On-a-ChipPharmacokineticsDrug membrane transportersProximal tubule-On-a-ChipDrug-Drug InteractionsDrug-Endogenous metabolite Interactions |
| spellingShingle | Isy Petit Quentin Faucher Jean-Sébastien Bernard Perrine Giunchi Antoine Humeau François-Ludovic Sauvage Pierre Marquet Nicolas Védrenne Florent Di Meo Proximal tubule-on-chip as a model for predicting cation transport and drug transporter dynamics Scientific Reports Organ-On-a-Chip Pharmacokinetics Drug membrane transporters Proximal tubule-On-a-Chip Drug-Drug Interactions Drug-Endogenous metabolite Interactions |
| title | Proximal tubule-on-chip as a model for predicting cation transport and drug transporter dynamics |
| title_full | Proximal tubule-on-chip as a model for predicting cation transport and drug transporter dynamics |
| title_fullStr | Proximal tubule-on-chip as a model for predicting cation transport and drug transporter dynamics |
| title_full_unstemmed | Proximal tubule-on-chip as a model for predicting cation transport and drug transporter dynamics |
| title_short | Proximal tubule-on-chip as a model for predicting cation transport and drug transporter dynamics |
| title_sort | proximal tubule on chip as a model for predicting cation transport and drug transporter dynamics |
| topic | Organ-On-a-Chip Pharmacokinetics Drug membrane transporters Proximal tubule-On-a-Chip Drug-Drug Interactions Drug-Endogenous metabolite Interactions |
| url | https://doi.org/10.1038/s41598-025-85653-4 |
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