@article {Sugimoto8, author = {Hiroshi Sugimoto and Hideki Hirabayashi and Yoshiaki Kimura and Atsutoshi Furuta and Nobuyuki Amano and Toshiya Moriwaki}, title = {Quantitative Investigation of the Impact of P-Glycoprotein Inhibition on Drug Transport across Blood-Brain Barrier in Rats}, volume = {39}, number = {1}, pages = {8--14}, year = {2011}, doi = {10.1124/dmd.110.035774}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {The magnitude of P-glycoprotein [(P-gp)/multidrug resistance protein 1 (MDR1)]-mediated drug-drug interaction (DDI) at the blood-brain barrier (BBB) in rats was estimated by in vitro-in vivo correlation (IVIVC). In in vitro studies, rat Mdr1a-expressing LLC-PK1 cells were examined for the evaluation of P-gp inhibitory activity using digoxin as a P-gp probe substrate. The in vitro Ki value was calculated using a modified corrected flux ratio that reflects the P-gp function. In in vivo studies, digoxin with or without P-gp inhibitors was administered to rats by constant intravenous infusion to evaluate the effect of P-gp inhibition on digoxin transport to the brain under steady-state conditions. In the presence of elacridar, the brain-to-plasma concentration ratio (Kp,brain) of digoxin was approximately 14 times the control value. However, no significant change in the Kp,brain was observed in the presence of clinically used P-gp inhibitors, with the exception of cyclosporine A. A positive correlation was found between the in vivo Kp,brain of digoxin and [I,unbound/Ki] (where I,unbound is the unbound plasma concentration of P-gp inhibitors). Compounds with [I,unbound/Ki] values of \>1 increased Kp,brain of digoxin in rats. In summary, we used a quantitative approach to evaluate the impact of P-gp-mediated DDI at the rat BBB. We successfully established the IVIVC, which indicated the potential DDI in the presence of potent P-gp inhibitors. On the basis of the IVIVC in rats and Ki values in human MDR1, we speculated that clinically used P-gp inhibitors do not cause DDI at the human BBB, because none of the compounds studied showed [I,unbound/Ki] values of \>1 at therapeutic doses.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/39/1/8}, eprint = {https://dmd.aspetjournals.org/content/39/1/8.full.pdf}, journal = {Drug Metabolism and Disposition} }