Application of a high‐resolution in vitro human MDR1‐MDCK assay and in vivo studies in preclinical species to improve prediction of CNS drug penetration

Abstract P‐glycoprotein (P‐gp, MDR1) is expressed at the blood–brain barrier (BBB) and restricts penetration of its substrates into the central nervous system (CNS). In vitro MDR1 assays are frequently used to predict the in vivo relevance of MDR1‐mediated efflux at the BBB. It has been well established that drug candidates with high MDR1 efflux ratios (ERs) display poor CNS penetration. Following a comparison of MDR1 transporter function between the MDR1‐MDCKI cell line from National Institutes of Health (NIH) and our internal MDR1‐MDCKII cell line, the former was found to provide better predictions of in vivo brain penetration than our in‐house MDR1‐MDCKII cell line. In particular, the NIH MDR1 assay has an improved sensitivity to differentiate the compounds with ERs of