@article {Trapa405, author = {Patrick E. Trapa and Matthew D. Troutman and Thomas Y. Lau and Travis T. Wager and Tristan S. Maurer and Nandini C. Patel and Mark A. West and John P. Umland and Anthony A. Carlo and Bo Feng and Jennifer L. Liras}, title = {In Vitro{\textendash}In Vivo Extrapolation of Key Transporter Activity at the Blood{\textendash}Brain Barrier}, volume = {47}, number = {4}, pages = {405--411}, year = {2019}, doi = {10.1124/dmd.118.083279}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Understanding the quantitative implications of P-glycoprotein and breast cancer resistance protein 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 to describe the in vivo unbound brain-to-plasma concentration ratio as a function of efflux activity measured in vitro. 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 physiologically based pharmacokinetic framework.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/47/4/405}, eprint = {https://dmd.aspetjournals.org/content/47/4/405.full.pdf}, journal = {Drug Metabolism and Disposition} }