Transporter study methodologies

Lai, Yurong

doi:10.1533/9781908818287.675

Transporters in Drug Discovery and Development 2013

DOI: 10.1533/9781908818287.675

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Transporter study methodologies

Yurong Lai¹

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Cited by 2 publications

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Fully automatic flow-based device for monitoring of drug permeation across a cell monolayer

et al. 2015

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A novel flow-programming setup based on the sequential injection principle is herein proposed for on-line monitoring of temporal events in cell permeation studies. The permeation unit consists of a Franz cell with its basolateral compartment mixed under mechanical agitation and thermostated at 37 °C. The apical compartment is replaced by commercially available Transwell inserts with a precultivated cell monolayer. The transport of drug substances across epithelial cells genetically modified with the P-glycoprotein membrane transporter (MDCKII-MDR1) is monitored on-line using rhodamine 123 as a fluorescent marker. The permeation kinetics of the marker is obtained in a fully automated mode by sampling minute volumes of solution from the basolateral compartment in short intervals (10 min) up to 4 h. The effect of a P-glycoprotein transporter inhibitor, verapamil as a model drug, on the efficiency of the marker transport across the cell monolayer is thoroughly investigated. The analytical features of the proposed flow method for cell permeation studies in real time are critically compared against conventional batch-wise procedures and microfluidic devices.

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Fully automatic flow-based device for monitoring of drug permeation across a cell monolayer

et al. 2015

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Practical Application of Rodent Transporter Knockout Models to Assess Brain Penetration in Drug Discovery

Eneberg

Jones

Jensen

et al. 2022

DMBL

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Background & Objective: Compound X is a drug candidate for the treatment of neurodegenerative diseases. Its brain distribution was evaluated as part of the lead identification and optimization of early drug discovery. Methods: The brain distribution of compound X was studied in genetic transporter knockout rodent models, in vivo models with a chemical inhibitor and in vitro transporter cell systems. Results: Compound X was found to be a substrate for human Breast Cancer-Resistance Protein (BCRP) in vitro (efflux ratio 8.1) and rodent Bcrp in vivo (Kp,uuKO/Kp,uuWT = 0.15/0.057 = 2.7, p < 0.05) but not a substrate for human P-glycoprotein (P-gp) in vitro (efflux ratio 1.0) nor rodent P-gp in vivo (Kp,uuKO/Kp,uuWT = 0.056/0.051 = 1.1, p > 0.05). When both transporters were knocked out in vivo, Kp,uu increased to 0.51 ± 0.02. Similar patterns observed across compounds with related chemistry corroborated structure-activity relationship. Conclusion: While in vitro assays showed compound X to be a substrate for human BCRP and not P-gp, in vivo studies indicated a synergistic effect between rodent efflux transporters. However, this only accounted for ~50% of restricted BBB-transport, suggesting involvement from other efflux transporters. Given Kp,uu is a key criterion for assessing technical quality of CNS candidates before progression into clinical development, it is important to identify relevant screening assays for a better understanding of low Kp,uu and brain distribution in pre-clinical models for translation to humans.

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Transporter study methodologies

Cited by 2 publications

References 146 publications

Fully automatic flow-based device for monitoring of drug permeation across a cell monolayer

Fully automatic flow-based device for monitoring of drug permeation across a cell monolayer

Practical Application of Rodent Transporter Knockout Models to Assess Brain Penetration in Drug Discovery

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