| Title |
Screening of Drug-Transporter Interactions in a 3D Microfluidic Renal Proximal Tubule on a Chip
|
|---|---|
| Published in |
The AAPS Journal, July 2018
|
| DOI | 10.1208/s12248-018-0247-0 |
| Pubmed ID | |
| Authors |
Jelle Vriend, Tom T. G. Nieskens, Marianne K. Vormann, Bartholomeus T. van den Berge, Angelique van den Heuvel, Frans G. M. Russel, Laura Suter-Dick, Henriëtte L. Lanz, Paul Vulto, Rosalinde Masereeuw, Martijn J. Wilmer |
| Abstract |
Drug-transporter interactions could impact renal drug clearance and should ideally be detected in early stages of drug development to avoid toxicity-related withdrawals in later stages. This requires reliable and robust assays for which current high-throughput screenings have, however, poor predictability. Kidney-on-a-chip platforms have the potential to improve predictability, but often lack compatibility with high-content detection platforms. Here, we combined conditionally immortalized proximal tubule epithelial cells overexpressing organic anion transporter 1 (ciPTEC-OAT1) with the microfluidic titer plate OrganoPlate to develop a screenings assay for renal drug-transporter interactions. In this platform, apical localization of F-actin and intracellular tight-junction protein zonula occludens-1 (ZO-1) indicated appropriate cell polarization. Gene expression levels of the drug transporters organic anion transporter 1 (OAT1; SLC22A6), organic cation transporter 2 (OCT2; SLC22A2), P-glycoprotein (P-gp; ABCB1), and multidrug resistance-associated protein 2 and 4 (MRP2/4; ABCC2/4) were similar levels to 2D static cultures. Functionality of the efflux transporters P-gp and MRP2/4 was studied as proof-of-concept for 3D assays using calcein-AM and 5-chloromethylfluorescein-diacetate (CMFDA), respectively. Confocal imaging demonstrated a 4.4 ± 0.2-fold increase in calcein accumulation upon P-gp inhibition using PSC833. For MRP2/4, a 3.0 ± 0.2-fold increased accumulation of glutathione-methylfluorescein (GS-MF) was observed upon inhibition with a combination of PSC833, MK571, and KO143. Semi-quantitative image processing methods for P-gp and MRP2/4 was demonstrated with corresponding Z'-factors of 0.1 ± 0.3 and 0.4 ± 0.1, respectively. In conclusion, we demonstrate a 3D microfluidic PTEC model valuable for screening of drug-transporter interactions that further allows multiplexing of endpoint read-outs for drug-transporter interactions and toxicity. |
X Demographics
The data shown below were collected from the profiles of 5 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Czechia | 1 | 20% |
| Netherlands | 1 | 20% |
| Unknown | 3 | 60% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 5 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 142 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 142 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 27 | 19% |
| Student > Master | 20 | 14% |
| Student > Bachelor | 15 | 11% |
| Researcher | 12 | 8% |
| Student > Doctoral Student | 6 | 4% |
| Other | 18 | 13% |
| Unknown | 44 | 31% |
| Readers by discipline | Count | As % |
|---|---|---|
| Biochemistry, Genetics and Molecular Biology | 26 | 18% |
| Engineering | 17 | 12% |
| Pharmacology, Toxicology and Pharmaceutical Science | 15 | 11% |
| Medicine and Dentistry | 12 | 8% |
| Agricultural and Biological Sciences | 10 | 7% |
| Other | 15 | 11% |
| Unknown | 47 | 33% |
Attention Score in Context
This research output has an Altmetric Attention Score of 5. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 01 August 2018.
All research outputs
#6,432,371
of 23,098,660 outputs
Outputs from The AAPS Journal
#354
of 1,297 outputs
Outputs of similar age
#111,481
of 330,323 outputs
Outputs of similar age from The AAPS Journal
#2
of 14 outputs
Altmetric has tracked 23,098,660 research outputs across all sources so far. This one has received more attention than most of these and is in the 72nd percentile.
So far Altmetric has tracked 1,297 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 6.0. This one has gotten more attention than average, scoring higher than 72% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 330,323 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 66% of its contemporaries.
We're also able to compare this research output to 14 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 85% of its contemporaries.