Quantitative investigation of the impact of P-glycoprotein inhibition on drug transport across blood-brain barrier in rats.
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 K(i) 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 (K(p,brain)) of digoxin was approximately 14 times the control value. However, no significant change in the K(p,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 K(p,brain) of digoxin and [I(,unbound)/K(i)] (where I(,unbound) is the unbound plasma concentration of P-gp inhibitors). Compounds with [I(,unbound)/K(i)] values of >1 increased K(p,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 K(i) 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)/K(i)] values of >1 at therapeutic doses.
Discovery Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan. sugimoto_hiroshi1@takeda.co.jp
Hiroshi
H
Sugimoto
Hideki
H
Hirabayashi
Yoshiaki
Y
Kimura
Atsutoshi
A
Furuta
Nobuyuki
N
Amano
Toshiya
T
Moriwaki
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000166:Acridines / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain; D016572:Cyclosporine / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D004077:Digoxin / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D018374:LLC-PK1 Cells; D008297:Male; D051381:Rats; D013552:Swine; D044005:Tetrahydroisoquinolines / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D004791:Enzyme Inhibitors; D044005:Tetrahydroisoquinolines; D004077:Digoxin; D016572:Cyclosporine; C083501:Elacridar