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Molecules 2016, 21(3), 300; doi:10.3390/molecules21030300

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

1,2
,
2
,
2,* , 1,* , 2
and
2
1
School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
2
Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China
*
Authors to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 11 January 2016 / Revised: 24 February 2016 / Accepted: 25 February 2016 / Published: 2 March 2016
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [1512 KB, uploaded 2 March 2016]   |  

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. View Full-Text
Keywords: paeoniflorin; ligustilide; senkyunolide I; senkyunolide A; blood–brain barrier; P-gp paeoniflorin; ligustilide; senkyunolide I; senkyunolide A; blood–brain barrier; P-gp
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MDPI and ACS Style

Hu, P.-Y.; Liu, D.; Zheng, Q.; Wu, Q.; Tang, Y.; Yang, M. 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. Molecules 2016, 21, 300.

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