title: Elucidation of Transport Mechanism of Paeoniflorin and the Influence of Ligustilide, Senkyunolide I and Senkyunolide A on Paeoniflorin Transport through Mdck-Mdr1 Cells as Blood-Brain Barrier in Vitro Model.
abstract: The objectives of the present investigation were to: (1) elucidate the transport mechanism of paeoniflorin (PF) across MDCK-MDR1 monolayers; and (2) evaluate the effect of ligustilide (LIG), senkyunolide I (SENI) and senkyunolide A (SENA) on the transport of PF through blood-brain barrier so as to explore the enhancement mechanism. Transport studies of PF were performed in both directions, from apical to basolateral side (A→B) and from basolateral to apical sides (B→A). Drug concentrations were analyzed by LC-MS/MS. PF showed relatively poor absorption in MDCK-MDR1 cells, apparent permeability coefficients (Papp) ranging from 0.587 × 10(-6) to 0.705 × 10(-6) cm/s. In vitro experiments showed that the transport of PF in both directions was concentration dependent and not saturable. The B→A/A→B permeability ER of PF was more than 2 in the MDCK-MDR1 cells, which indicated that the transport mechanism of PF might be passive diffusion as the dominating process with the active transportation mediated mechanism involved. The increased Papp of PF in A→B direction by EDTA-Na₂ suggested that PF was absorbed via the paracellular route. The P-gp inhibitor verapamil could significantly increase the transport of PF in A→B direction, and ER decreased from 2.210 to 0.690, which indicated that PF was P-gp substance. The transport of PF in A→B direction significantly increased when co-administrated with increasing concentrations of LIG, SENI and SENA. An increased cellular accumulation of Rho 123 and Western blot analysis indicated that LIG, SENI and SENA had increased the transport of PF in the BBB models attribute to down-regulate P-gp expression. A decrease in transepithelial electrical resistance (TEER) during the permeation experiment can be explained by the modulation and opening of the tight junctions caused by the permeation enhancer LIG, SENI and SENA.
authors.affiliation: School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China. hpy820515@126.com.|Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China. hpy820515@126.com.
authors.forename: Peng-Yi
authors.initials: PY
authors.lastname: Hu
authors.affiliation: Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China. 18070142107@163.com.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China. zhengqin912006@163.com.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China. qwu@vip.sina.com.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China. ty505783@163.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China. yangming16@126.com.
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000818:Animals; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D005960:Glucosides / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D061985:Madin Darby Canine Kidney Cells; D015394:Molecular Structure; D039821:Monoterpenes / Q000737:chemistry / Q000493:pharmacokinetics*; D006027:Glycosides
chemical_list: D015107:4-Butyrolactone; D018435:ATP Binding Cassette Transporter, Subfamily B; D001572:Benzofurans; D005960:Glucosides; D039821:Monoterpenes; C513055:ABCB1 protein, human; C576743:senkyunolide I; C015423:peoniflorin; D006027:Glycosides; C027820:ligustilide; C045855:3-N-butyl-4,5-dihydrophthalide
keywords: P-gp; blood–brain barrier; ligustilide; paeoniflorin; senkyunolide A; senkyunolide I