title: Retrospective analysis of P-glycoprotein-mediated drug-drug interactions at the blood-brain barrier in humans.
abstract: To date, the in vitro-in vivo correlation (IVIVC) of P-glycoprotein (P-gp)-mediated drug-drug interaction (DDI) at the blood-brain barrier (BBB) in rats indicated that the cutoff value to significantly affect the brain penetration of digoxin was [I,unbound/Ki] of 1, where I,unbound is the unbound plasma concentration of P-gp inhibitors. On the basis of the IVIVC in rats, we speculated that clinically used P-gp inhibitors do not cause DDI at the human BBB, because none of the compounds studied was [I,unbound/Ki]>1 at therapeutic doses. Recently, positron emission tomography studies with P-gp substrates, such as [(11)C]verapamil, [(11)C]N-desmethyl loperamide, and [(11)C]loperamide, together with potent P-gp inhibitors, have indicated that increases in the influx rate constant for brain entry were observed in humans. Therefore, we aimed to retrospectively analyze the results of P-gp-mediated DDIs with in vitro P-gp inhibition assays and to confirm the appropriate cutoff value. In vitro P-gp inhibition assays using verapamil, N-desmethyl loperamide, and loperamide as P-gp probe substrates were performed in human multidrug resistance protein 1-expressing LLC-PK1 cells. The efflux ratios decreased in the presence of P-gp inhibitors, and the Ki of tariquidar was 10 nmol/L, regardless of probe substrates. Taking the in vitro Ki and unbound plasma concentrations in clinical DDI studies together, the criterion [I,unbound/Ki] of 1 was an appropriate cutoff limit to observe significant P-gp-mediated DDI at the BBB in humans. On the other hand, no significant DDI was observed in cases in which [I,unbound/Ki] was less than 0.1. This criterion was comparable to the previous IVIVC result in rats.
authors: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. hiroshi.sugimoto1@takeda.com
authors: Hiroshi
authors: H
authors: Sugimoto
authors: Hideki
authors: H
authors: Hirabayashi
authors: Nobuyuki
authors: N
authors: Amano
authors: Toshiya
authors: T
authors: Moriwaki
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000201:enzymology; D004347:Drug Interactions; D006801:Humans; D018374:LLC-PK1 Cells; D008139:Loperamide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D011804:Quinolines / Q000494:pharmacology; D013552:Swine; D014700:Verapamil / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011804:Quinolines; C419149:N-demethylloperamide; D008139:Loperamide; D014700:Verapamil; C402343:tariquidar