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The objectives of this study were to (1) characterize MDR-MDCK monolayers as an in vitro model to predict brain uptake potential; (2) examine the ability of MDR-MDCK monolayers to identify the brain uptake potential of compounds that interact with P-glycoprotein (P-gp). The study measured the bi-directional transport of 28 compounds across MDR-MDCK monolayers. The brain uptake of a subset of the compounds was determined in the rat brain perfusion model. Drug concentrations were analyzed by LC–MS–MS. CNS-positive drugs exhibited absorptive permeability coefficients (Papp, A–B) values ranging from 3.4 × 10−6 to 20.2 × 10−6 cm/s; whereas CNS-negative drugs showed Papp (A–B) ranging from 0.03 × 10−6 to 0.83 × 10−6 cm/s. Inhibition of P-gp by cyclosporin A (CsA) significantly reduced secretory flux of compounds known to be P-pg substrates, but only enhanced the absorptive flux of compounds with high efflux ratio (>100). In vitro results were confirmed by brain perfusion studies on selected compounds. MDR-MDCK monolayers can be used to classify compounds into CNS-positive or CNS-negative based on the permeability coefficients (Papp, A–B). Under our experimental conditions, compounds with Papp (A–B) >3 × 10−6 cm/s have high brain uptake potential; compounds with Papp (A–B) < 1 × 10−6 cm/s are unable to penetrate the blood–brain barrier (BBB); the brain uptake of compounds with Papp (A–B) < 1 × 10−6 cm/s and a P-gp-mediated efflux ratio of >100 may be enhanced by inhibiting P-gp.