TY - JOUR T1 - In vitro-In vivo extrapolation of key transporter activity at the blood-brain barrier JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.118.083279 SP - dmd.118.083279 AU - Patrick E Trapa AU - Matthew D Troutman AU - Thomas Y Lau AU - Travis T Wager AU - Tristan S Maurer AU - Nandini C Patel AU - Mark A West AU - John P Umland AU - Anthony A Carlo AU - Bo Feng AU - Jennifer L Liras Y1 - 2019/01/01 UR - http://dmd.aspetjournals.org/content/early/2019/01/25/dmd.118.083279.abstract N2 - Understanding the quantitative implications of P-gp and BCRP efflux is a key hurdle in the design of effective, centrally-acting or centrally restricted therapeutics. Previously, a comprehensive physiologically-based pharmacokinetic model was developed which describes in vivo unbound brain-to-plasma concentration ratio as a function of efflux activity measured in vitro (Trapa et al., 2016). In the present work, the predictive utility of this framework was examined through application to in vitro and in vivo data generated on 133 unique compounds across three preclinical species. Two approaches were examined for the scaling of efflux activity to in vivo, namely; relative expression as determined by independent proteomics measurements and relative activity as determined via fitting the in vivo neuropharmacokinetic data. The results with both approaches indicate that in vitro efflux data can be used to accurately predict the degree of brain penetration across species within the context of the proposed PBPK framework. ER -