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Cho, Moo J.; Thompson, David P.; Cramer, Clay T.; Vidmar, Thomas J.; Scieszka, Jeffrey F.

doi:10.1023/a:1015807904558

Cited by 171 publications

(29 citation statements)

References 14 publications

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“…The MDCK (NBL-2) cell line, derived from dog kidney, is capable of forming a very tight polarized barrier within 4 to 6 days of growth. 27 , and also expresses many influx and efflux drug transporters 28 . One of the major advantages of MDCK (NBL-2) cells over other epithelial cells is short cultivation time that results in significant reduction in labor as well as chances of cell contamination.…”

Section: Discussionmentioning

confidence: 99%

Pigmented-MDCK (P-MDCK) Cell Line with Tunable Melanin Expression: An in Vitro Model for the Outer Blood–Retinal Barrier

2012

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Purpose Retinal pigment epithelium, which forms the outer blood-retinal-barrier, is a critical barrier for transport of drugs to the retina. The purpose of this study was to develop a pigmented MDCK (P-MDCK) cell line as a rapidly established in vitro model for the outer blood-retinal-barrier to assess the influence of melanin pigment on solute permeability. Methods A melanin synthesizing P-MDCK cell line was developed by lentiviral transduction of human tyrosinase and p-protein genes in MDCK (NBL-2) cells. Melanin content, tyrosinase activity (conversion of L-dopa to dopachrome), and transepithelial electrical resistance (TEER) were measured. Expression of tyrosinase protein and p-protein in P-MDCK cells was confirmed by confocal microscopy. Effect of L-tyrosine (0 to 2 mM) in culture medium on melanin synthesis in P-MDCK cells was evaluated. Cell uptake and transepithelial transport of pigment-binding chloroquine (Log D = 1.59) and a negative control salicylic acid (Log D = −1.14) were investigated. Results P-MDCK cells expressed tyrosinase and p-protein. Tyrosinase activity was 4.5 fold higher in P-MDCK cells as compared to wild-type MDCK cells. The transepithelial electrical resistance stabilized by day 4 in both cell types, with the TEER being 871 ± 30 and 876 ± 53 Ω.cm2 for P-MDCK and wild-type cells, respectively. Melanin content in P-MDCK cells depended on the concentration of L-tyrosine in culture medium, and increased from 3 to 54 µg/mg protein with an increase in L-tyrosine content from 0 to 2 mM. When the cells were grown in 2 mM L-tyrosine, uptake of chloroquine was 2.3 fold higher and the transepithelial transport was 2.2 fold lower in P-MDCK cells when compared to wild-type MDCK cells. No significant difference was observed for both cell uptake and transport of salicylic acid. Conclusions We developed a P-MDCK cell line with tunable melanin synthesis as a rapidly developing surrogate for retinal pigment epithelium.

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Section: Discussionmentioning

confidence: 99%

Pigmented-MDCK (P-MDCK) Cell Line with Tunable Melanin Expression: An in Vitro Model for the Outer Blood–Retinal Barrier

2012

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“… + Perm_chrom_p.perm_score An inhouse PLS-Discriminant analysis model which predicts permeability and oral absorption of compounds. + MDCK2.Perm_pH74_nm_sec MDCK2.Perm_pH64_nm_sec Inhouse QSAR models which predict passive permeability across a madine darby canine kidney (MDCK) cell monolayer ( 31 ) with donor solutions buffered at pH7.4 and pH6.4. + Pgp_v31.Pgp_Score An inhouse PLS-Discriminant analysis model which predicts the likelihood of a compound being a substrate for the ABC active efflux transporter P-glycoprotein.…”

Section: Resultsmentioning

confidence: 99%

Development of a Novel Quantitative Structure-Activity Relationship Model to Accurately Predict Pulmonary Absorption and Replace Routine Use of the Isolated Perfused Respiring Rat Lung Model

et al. 2016

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PurposeWe developed and tested a novel Quantitative Structure-Activity Relationship (QSAR) model to better understand the physicochemical drivers of pulmonary absorption, and to facilitate compound design through improved prediction of absorption. The model was tested using a large array of both existing and newly designed compounds.MethodsPulmonary absorption data was generated using the isolated perfused respiring rat lung (IPRLu) model for 82 drug discovery compounds and 17 marketed drugs. This dataset was used to build a novel QSAR model based on calculated physicochemical properties. A further 9 compounds were used to test the model’s predictive capability.ResultsThe QSAR model performed well on the 9 compounds in the “Test set” with a predicted versus observed correlation of R2 = 0.85, and >65% of compounds correctly categorised. Calculated descriptors associated with permeability and hydrophobicity positively correlated with pulmonary absorption, whereas those associated with charge, ionisation and size negatively correlated.ConclusionsThe novel QSAR model described here can replace routine generation of IPRLu model data for ranking and classifying compounds prior to synthesis. It will also provide scientists working in the field of inhaled drug discovery with a deeper understanding of the physicochemical drivers of pulmonary absorption based on a relevant respiratory compound dataset.

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“…Finally, the Madin–Darby canine kidney (MDCK) cells are a nonintestinal cell line derived from kidney tubules, and used to study cell permeability and infection . MDCK cells can polarize into a confluent monolayer forming tight junctions, and differentiate rapidly (between 3 and 6 days) .…”

Section: In Vitro Cell Culture Modelsmentioning

confidence: 99%

Models of the Gut for Analyzing the Impact of Food and Drugs

Fois

Schindeler

et al. 2019

Adv Healthcare Materials

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The human intestine is the primary organ responsible for the uptake of nutrients and water, and this is facilitated by its complex structure that features a large surface area. With an average total length of around seven meters, including both small and large intestine, it connects the stomach to the rectum while enabling absorption in a specialized manner. At a cellular level, the gut epithelium is critical in selective transport to the bloodstream. The finger-like projections of the intestinal epithelium Models of the human gastrointestinal tract (GIT) can be powerful tools for examining the biological interactions of food products and pharmaceuticals. This can be done under normal healthy conditions or using models of disease-many of which have no curative therapy. This report outlines the field of gastrointestinal modeling, with a particular focus on the intestine. Traditional in vivo animal models are compared to a range of in vitro models. In vitro systems are elaborated over time, recently culminating with microfluidic intestines-on-chips (IsOC) and 3D bioengineered models. Macroscale models are also reviewed for their important contribution in the microbiota studies. Lastly, it is discussed how in silico approaches may have utility in predicting and interpreting experimental data. The various advantages and limitations of the different systems are contrasted. It is posited that only through complementary use of these models will salient research questions be able to be addressed.

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Cited by 171 publications

References 14 publications

Pigmented-MDCK (P-MDCK) Cell Line with Tunable Melanin Expression: An in Vitro Model for the Outer Blood–Retinal Barrier

Pigmented-MDCK (P-MDCK) Cell Line with Tunable Melanin Expression: An in Vitro Model for the Outer Blood–Retinal Barrier

Development of a Novel Quantitative Structure-Activity Relationship Model to Accurately Predict Pulmonary Absorption and Replace Routine Use of the Isolated Perfused Respiring Rat Lung Model

Models of the Gut for Analyzing the Impact of Food and Drugs

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