Blood-Brain Barrier (BBB) Pharmacoproteomics: Reconstruction of In Vivo Brain Distribution of 11 P-Glycoprotein Substrates Based on the BBB Transporter Protein Concentration, In Vitro Intrinsic Transport Activity, and Unbound Fraction in Plasma and Brain in Mice

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 339; no. 2; pp. 579 - 588
• Main Authors: Uchida, Yasuo, Ohtsuki, Sumio, Kamiie, Junichi, Terasaki, Tetsuya
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2011
• Subjects: Animals; ATP Binding Cassette Transporter, Subfamily B - metabolism; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters - metabolism; Biological Transport, Active - drug effects; Blood-Brain Barrier - metabolism; Brain - drug effects; Brain - metabolism; Dogs; Drug Discovery; Drug Evaluation, Preclinical; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacokinetics; Kidney; LLC-PK1 Cells; Male; Mice; Models, Biological; Pharmaceutical Preparations - blood; Pharmaceutical Preparations - metabolism; Proteomics - methods; Quinidine - metabolism; Quinidine - pharmacokinetics; Swine; fu,plasma; BBB; P-gp; mdr1a; KO; Kp,uu,brain; CNS; ECF; MRM; oatp2; bcrp; LC-MS/MS; MDR1; QTAP; Papp; fu,brain; PPx; MDCK; Kp brain; WT; HPLC; GR205171

The purpose of this study was to examine whether in vivo drug distribution to the brain can be reconstructed by integrating P-glycoprotein (P-gp)/mdr1a expression levels, P-gp in vitro activity, and drug unbound fractions in mouse plasma and brain. For 11 P-gp substrates, in vitro P-gp transport act...