PT - JOURNAL ARTICLE AU - Hiroshi Sugimoto AU - Hideki Hirabayashi AU - Yoshiaki Kimura AU - Atsutoshi Furuta AU - Nobuyuki Amano AU - Toshiya Moriwaki TI - Quantitative Investigation of the Impact of P-Glycoprotein Inhibition on Drug Transport across Blood-Brain Barrier in Rats AID - 10.1124/dmd.110.035774 DP - 2011 Jan 01 TA - Drug Metabolism and Disposition PG - 8--14 VI - 39 IP - 1 4099 - http://dmd.aspetjournals.org/content/39/1/8.short 4100 - http://dmd.aspetjournals.org/content/39/1/8.full SO - Drug Metab Dispos2011 Jan 01; 39 AB - 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.