Validation of Human MDR1-MDCK and BCRP-MDCK Cell Lines to Improve the Prediction of Brain Penetration

Journal of Pharmaceutical Sciences
Bo FengJennifer L Liras

Abstract

It is of great challenge to predict human brain penetration for substrates of multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), 2 major efflux transporters at blood-brain barrier. Thus, a physiologically based pharmacokinetic (PBPK) model with the incorporation of in vitro MDR1 and BCRP transporter function data and transporter protein expression levels has been developed. As such, it is crucial to generate MDR1 and BCRP substrate data with a high fidelity. In this study, 2 widely used human MDR1 cell lines from Borst and National Institutes of Health laboratories were evaluated using rodent brain penetration data, and the study suggested that the MDR1 expressed in Madin-Darby canine kidney (MDCK) cell line from National Institutes of Health laboratory predicted brain penetration better, particularly for compounds with a high passive permeability. In addition, human BCRP-MDCK cell line with 1 μM PSC833, a specific MDR1 inhibitor, demonstrated the ability to identify BCRP substrates without the confounding of endogenous canine Mdr1. Comparison of human BCRP and mouse Bcrp transporter functions revealed that the functional differences of BCRP between the 2 species is minimal. The incorporation of ...Continue Reading

Citations

Mar 3, 2021·ACS Chemical Neuroscience·Nandini C PatelTravis T Wager
Jun 1, 2020·Journal of Controlled Release : Official Journal of the Controlled Release Society·Alexander KominKalina Hristova
Feb 25, 2021·Biopharmaceutics & Drug Disposition·Jonathan J NovakLi Di
Jul 17, 2021·ACS Medicinal Chemistry Letters·Nicky HwangYanming Du
Aug 27, 2021·Clinical Pharmacokinetics·Robert HermannAlain Munafo
Jul 15, 2020·Journal of Medicinal Chemistry·Longbin LiuCelia Dominguez
Jan 26, 2021·ACS Medicinal Chemistry Letters·Thomas O SchraderDaniel S Lorrain
Aug 14, 2020·Journal of Medicinal Chemistry·Brian S GerstenbergerStephen W Wright
Dec 31, 2021·Journal of Medicinal Chemistry·Mitchell H KeylorPeter H Fuller

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