title: P-Glycoprotein (ABCB1) limits the brain distribution of YQA-14, a novel dopamine D3 receptor antagonist.
abstract: YQA-14 is a promising agent for treating addiction to cocaine and opioids. However, previous studies have showed there is marked contrast between the relatively small differences in pharmacological action in vivo and the large differences in their respective receptor binding properties in vitro. We hypothesized that the conflict between the in vivo and in vitro outcomes was attributable to poor brain exposure to YQA-14 caused by drug efflux transporters. To address this issue, we investigated the directional flux of YQA-14 across Caco-2 cells at 37°C or 4°C and the bidirectional transport in the presence and absence of transporter chemical inhibitors. These phenomena were further investigated by an in vivo determination of the brain and blood pharmacokinetics (PK) profile of YQA-14 following intraperitoneal administration with and without inhibitor. The efflux ratio of YQA-14 on Caco-2 cell monolayers was 2.39 and the efflux was temperature-dependent. When co-incubated with GF120918 or LY335979, the efflux of YQA-14 was markedly decreased. However, there was no significant difference in the permeability of YQA-14 when the cells were treated with Ko143. In vivo experiments showed that the brain-to-plasma ratio increased by more than 75-fold and 20-fold with co-administration of GF120918 and LY335979, respectively. Use of Ko143 did not change the brain-to-blood ratio of YQA-14. The results indicate that the brain distribution of YQA-14 was restricted because of active efflux transport at the blood brain barrier. In addition, P-glycoprotein (P-gp) played a dominant role in limiting the distribution of YQA-14 to the brain.
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of PLA.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Wang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Zhuang
authors.forename: Zhenqing
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000166:Acridines / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D001583:Benzoxazoles / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D018938:Caco-2 Cells; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D054659:Diketopiperazines; D018492:Dopamine Antagonists / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D006207:Half-Life; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D051379:Mice; D010539:Permeability / Q000187:drug effects; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D011804:Quinolines / Q000494:pharmacology; D012372:ROC Curve; D013696:Temperature; D044005:Tetrahydroisoquinolines / Q000494:pharmacology
chemical_list: C541506:3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D001583:Benzoxazoles; D003986:Dibenzocycloheptenes; D054659:Diketopiperazines; D018492:Dopamine Antagonists; D006576:Heterocyclic Compounds, 4 or More Rings; D010879:Piperazines; D011804:Quinolines; D044005:Tetrahydroisoquinolines; C571881:YQA14; C095179:zosuquidar trihydrochloride; D000241:Adenosine; C083501:Elacridar