RT Journal Article
SR Electronic
T1 In Vitro–In Vivo Extrapolation of Key Transporter Activity at the Blood–Brain Barrier
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 405
OP 411
DO 10.1124/dmd.118.083279
VO 47
IS 4
A1 Patrick E. Trapa
A1 Matthew D. Troutman
A1 Thomas Y. Lau
A1 Travis T. Wager
A1 Tristan S. Maurer
A1 Nandini C. Patel
A1 Mark A. West
A1 John P. Umland
A1 Anthony A. Carlo
A1 Bo Feng
A1 Jennifer L. Liras
YR 2019
UL http://dmd.aspetjournals.org/content/47/4/405.abstract
AB 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.