ArticlePharmaceutical research2020
Characterization and Validation of Canine P-Glycoprotein-Deficient MDCK II Cell Lines for Efflux Substrate Screening.
Article in Pharmaceutical research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 19 citations in OpenAlex.
- Design and Exploration of a Tricyclic Series of CNS-Penetrant CD38 Small Molecule Inhibitors.ACS medicinal chemistry letters · 2026Article
- Functional Characterization of the Cat and Dog Wild-Type and Mutant MDR1 Carrier Proteins and Frequency of the MDR1 Gene Mutation in 800 Cats From Germany.Journal of veterinary pharmacology and therapeutics · 2026Article
- Predicting seizure liability of small molecules using an in vitro multi-electrode array based assay coupled with modeling of brain disposition.Current research in toxicology · 2025Article
- Establishment and transcriptomic characterization of canine organoids from multiple tissues.Frontiers in cell and developmental biology · 2025Article
- Conquering the beyond Rule of Five Space with an Optimized High-Throughput Caco-2 Assay to Close Gaps in Absorption Prediction.Pharmaceutics · 2024Article
- The Trends and Future Prospective of In Silico Models from the Viewpoint of ADME Evaluation in Drug Discovery.Pharmaceutics · 2023Review
- Challenges in Permeability Assessment for Oral Drug Product Development.Pharmaceutics · 2023Review
- CRISPR/Cas9 targeting liposomes knocked down multidrug resistance proteins in brain endothelial cells as a model to predict potential pharmacoresistance.Colloids and surfaces. B, Biointerfaces · 2023Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeWe characterized three canine P-gp (cP-gp) deficient MDCKII cell lines. Their relevance for identifying efflux transporter substrates and predicting limitation of brain penetration were evaluated. In addition, we discuss how compound selection can be done in drug discovery by using these cell systems.
methodhMDR1, hBCRP-transfected, and non-transfected MDCKII ZFN cells (all with knock-down of endogenous cP-gp) were used for measuring permeability and efflux ratios for substrates. The compounds were also tested in MDR1_Caco-2 and BCRP_Caco-2, each with a double knock-out of BCRP/MRP2 or MDR1/MRP2 transporters respectively. Efflux results were compared between the MDCK and Caco-2 models. Furthermore, in vitro MDR1_ZFN efflux data were correlated with in vivo unbound drug brain-to-plasma partition coefficient (K
resultsMDR1 and BCRP substrates are correctly classified and robust transporter affinities with control substrates are shown. Cell passage mildly influenced mRNA levels of transfected transporters, but the transporter activity was proven stable for several years. The MDCK and Caco-2 models were in high consensus classifying same efflux substrates. Approx. 80% of enlisted substances were correctly predicted with the MDR1_ZFN model for brain penetration.
conclusioncP-gp deficient MDCKII ZFN models are reliable tools to identify MDR1 and BCRP substrates and useful for predicting efflux liability for brain penetration.
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