PT  - JOURNAL ARTICLE
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
TI  - In vitro-In vivo extrapolation of key transporter activity at the blood-brain barrier
AID  - 10.1124/dmd.118.083279
DP  - 2019 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.118.083279
4099  - http://dmd.aspetjournals.org/content/early/2019/01/25/dmd.118.083279.short
4100  - http://dmd.aspetjournals.org/content/early/2019/01/25/dmd.118.083279.full
AB  - 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.