Proof-of-Concept Study of Drug Brain Permeability Between in Vivo Human Brain and an in Vitro iPSCs-Human Blood-Brain Barrier Model

被引:39
作者
Le Roux, Gwenaelle [1 ]
Jarray, Rafika [2 ,3 ]
Guyot, Anne-Cecile [1 ]
Pavoni, Serena [2 ]
Costa, Narciso [1 ]
Theodoro, Frederic [4 ]
Nassor, Ferid [2 ,3 ]
Pruvost, Alain [4 ]
Tournier, Nicolas [5 ]
Kiyan, Yulia [6 ]
Langer, Oliver [7 ,8 ]
Yates, Frank [2 ,3 ]
Deslys, Jean Philippe [2 ]
Mabondzo, Aloise [1 ]
机构
[1] Univ Paris Saclay, CEA, Serv Pharmacol & Immunoanal, F-91191 Gif Sur Yvette, France
[2] CEA, Serv Etud Prions & Infect Atyp, F-92265 Fontenay Aux Roses, France
[3] Sup Biotech, F-94800 Villejuif, France
[4] Univ Paris Saclay, INRA, CEA, SPI,Plateforme Smart MS, F-91191 Gif Sur Yvette, France
[5] Univ Paris Saclay, Serv Hosp Frederic Joliot, CNRS, INSERM,UMR 1023,IMIV,CEA,Univ Paris Sud, Orsay, France
[6] Hannover Med Sch, DE-30625 Hannover, Germany
[7] Med Univ Vienna, Dept Clin Pharmacol, A-1090 Vienna, Austria
[8] AIT Austrian Inst Technol GmbH, Preclin Mol Imaging, A-2444 Seibersdorf, Austria
关键词
POSITRON-EMISSION-TOMOGRAPHY; ENDOTHELIAL-CELLS; INHIBITION; STRATEGIES; TRANSPORT; DELIVERY; ABCG2; ABCB1; PET;
D O I
10.1038/s41598-019-52213-6
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The development of effective central nervous system (CNS) drugs has been hampered by the lack of robust strategies to mimic the blood-brain barrier (BBB) and cerebrovascular impairments in vitro. Recent technological advancements in BBB modeling using induced pluripotent stem cells (iPSCs) allowed to overcome some of these obstacles, nonetheless the pertinence for their use in drug permeation study remains to be established. This mandatory information requires a cross comparison of in vitro and in vivo pharmacokinetic data in the same species to avoid failure in late clinical drug development. Here, we measured the BBB permeabilities of 8 clinical positron emission tomography (PET) radioligands with known pharmacokinetic parameters in human brain in vivo with a newly developed in vitro iPSC-based human BBB (iPSC-hBBB) model. Our findings showed a good correlation between in vitro and in vivo drug brain permeability (R-2 = 0.83; P = 0.008) which contrasted with the limited correlation between in vitro apparent permeability for a set of 18 CNS/non-CNS compounds using the in vitro iPSCs-hBBB model and drug physicochemical properties. Our data suggest that the iPSC-hBBB model can be integrated in a flow scheme of CNS drug screening and potentially used to study species differences in BBB permeation.
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页数:11
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