title: Transport of active flavonoids, based on cytotoxicity and lipophilicity: an evaluation using the blood-brain barrier cell and Caco-2 cell models.
abstract: This in vitro study aims to evaluate and compare transmembrane transport of eight cardio-cerebrovascular protection flavonoids including puerarin, rutin, hesperidin, quercetin, genistein, kaempferol, apigenin and isoliquiritigenin via the rat blood-brain barrier cell and Caco-2 cell monolayer models, based on the data of cytotoxicity and lipophilicity. The cytotoxicity of the flavonoids to rat brain microvessel endothelial cell was determined by the MTT assay. The apparent permeability coefficients (Papp) of the flavonoids were calculated from the unilateral transport assays in Transwell system with simultaneous determination using a high performance liquid chromatography. The results showed that the cytotoxicity and oil-water partition coefficient of the flavonoids modified by the number and position of the glycoside and hydroxyl group were the key determinant for the transmembrane transport. The Papp values of the flavonoids reduced adversely when the numbers of glycoside and hydroxyl groups of the flavonoids increased accordingly. The tested flavonoids exhibited time-dependent Papp values in these models. The efflux mechanism related with P-glycoprotein also existed with the polar flavonoids; verapamil could enhance the permeation of rutin and quercetin via inhibition of P-glycoprotein. We propose that genistein and isoliquiritigenin with the permeation priority in vitro Caco-2 and BBB cell model could be better as the drug candidates for cardio-cerebral vascular protection. These findings provided important information for establishing the transport relationship for the flavonoid compounds and evaluating the potential oral bioavailability and brain distribution of the flavonoids.
authors.affiliation: Department of Pharmacology, Beijing Laboratory of Biomedical Detection and Instrument, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Beijing Laboratory of Biomedical Detection and Instrument, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Bai
authors.affiliation: Department of Pharmacology, Beijing Laboratory of Biomedical Detection and Instrument, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Beijing Laboratory of Biomedical Detection and Instrument, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Department of Pharmacology, Beijing Laboratory of Biomedical Detection and Instrument, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
authors.forename: Pinxiang
authors.initials: P
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Beijing Laboratory of Biomedical Detection and Instrument, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
authors.forename: Chenyang
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, Beijing Laboratory of Biomedical Detection and Instrument, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China. Electronic address: xuem@ccmu.edu.cn.
authors.forename: Ming
authors.initials: M
authors.lastname: Xue
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005419:Flavonoids / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D006801:Humans; D008297:Male; D055806:Microvessels / Q000378:metabolism; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005419:Flavonoids
keywords: Blood–brain barrier cell; Caco-2 cell; Cytotoxicity; Flavonoids; Transport