Abstract

P-glycoprotein (P-gp) is expressed at the blood-brain barrier (BBB) and restricts the penetration of its substrates into the central nervous system (CNS). In vitro substrate assessment for P-gp is frequently used to predict the in vivo relevance of P-gp-mediated efflux at the BBB. We have conducted a comprehensive review of literature focusing on the in vitro–in vivo correlation of P-gp efflux ratio (ER), and demonstrated that in vitro substrates of P-gp are also in vivo substrates at the BBB. It was of note that the in vitro ER in the MDCK-MDR1 cell line from National Institutes of Health was found to be a better predictor of in vivo ER than that from Netherlands Cancer Institute, with r² values of 0.813 and 0.531, respectively. Recently, a research group proposed that 98% of Biopharmaceutics Drug Disposition Classification System (BDDCS) class 1 drugs can penetrate the brain even when those compounds are shown as P-gp substrates in vitro. However, our data analysis suggested that in vitro ER can predict the in vivo brain penetration regardless of the class in BDDCS. Considering that very few marketed CNS drugs are in vivo substrates for P-gp, the in vitro substrate assessment of P-gp should be used in the early stages of drug discovery to select compounds that are most likely to penetrate the CNS to exert their pharmacologic action.