title: Mechanism of brain targeting by dexibuprofen prodrugs modified with ethanolamine-related structures.
abstract: The first molecular insights into how prodrugs modified with ethanolamine-related structures target the brain were generated using an in vitro BBB model and in situ perfusion technique. Prodrugs were delivered safely and efficiently to the brain through tight interaction with the anionic membrane of brain capillary endothelial cells, observed as a shift in zeta potential, followed by uptake into the cells. Prodrugs III and IV carrying primary and secondary amine modifications appeared to enter the brain via energy-independent passive diffusion. In contrast, besides the passive diffusion, prodrugs I and II carrying tertiary amine modifications also appeared to enter via an active process that was energy and pH dependent but was independent of sodium or membrane potential. This active process involved, at least in part, the pyrilamine-sensitive H(+)/OC antiporter, for which the N,N-diethyl-based compound II showed a much lower affinity than the N,N-dimethyl-based compound I, likely due to steric hindrance. These new insights into brain-targeting mechanisms may help guide efforts to design new prodrugs.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Gong
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Xun
authors.initials: X
authors.lastname: Sun
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D002196:Capillaries / Q000378:metabolism; D002460:Cell Line; D018920:Coculture Techniques; D004058:Diffusion; D016503:Drug Delivery Systems; D015195:Drug Design; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000378:metabolism; D004983:Ethanolamines / Q000737:chemistry / Q000494:pharmacology*; D007052:Ibuprofen / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology*; D011738:Pyrilamine / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000199:Actins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004983:Ethanolamines; D011355:Prodrugs; C539402:dexibuprofen; D011738:Pyrilamine; D007052:Ibuprofen