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Role of P-glycoprotein in limiting the brain penetration of glabridin, an active isoflavan from the root of Glycyrrhiza glabra.

Yu, Xi-Yong, Zhou, Zhi-Wei, Lin, Shu-Guang, Chen, Xiao, Yu, Xue-Qing, Liang, Jun, Duan, Wei, Wen, Jing-Yuan, Li, Xiao-Tian, Zhou, Shu-Feng, Chowbay, Balram, Chan, Eli, Cao, Jie, Li, Chun-Guang and Xue, Charlie Changli 2007, Role of P-glycoprotein in limiting the brain penetration of glabridin, an active isoflavan from the root of Glycyrrhiza glabra., Pharmaceutical research, vol. 24, no. 9, pp. 1668-1690, doi: 10.1007/s11095-007-9297-1.

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Title Role of P-glycoprotein in limiting the brain penetration of glabridin, an active isoflavan from the root of Glycyrrhiza glabra.
Formatted title Role of P-glycoprotein in limiting the brain penetration of glabridin, an active isoflavan from the root of Glycyrrhiza glabra.
Author(s) Yu, Xi-Yong
Zhou, Zhi-Wei
Lin, Shu-Guang
Chen, Xiao
Yu, Xue-Qing
Liang, Jun
Duan, WeiORCID iD for Duan, Wei
Wen, Jing-Yuan
Li, Xiao-Tian
Zhou, Shu-Feng
Chowbay, Balram
Chan, Eli
Cao, Jie
Li, Chun-Guang
Xue, Charlie Changli
Journal name Pharmaceutical research
Volume number 24
Issue number 9
Start page 1668
End page 1690
Publisher Springer Netherlands
Place of publication Delft, The Netherlands
Publication date 2007-09
ISSN 0724-8741
Keyword(s) brain-blood barrier
in situ brain perfusion
mdr1a knockout mouse
rat brain microvascular endothelial cell
Summary Purpose. Glabridin is a major active constituent of Glycyrrhiza glabra which is commonly used in the treatment of cardiovascular and central nervous system (CNS) diseases. Recently, we have found that glabridin is a substrate of P-glycoprotein (PgP/MDR1). This study aimed to investigate the role of PgP in glabridin penetration across the blood–brain barrier (BBB) using several in vitro and in vivo models.
Materials and Methods. Cultured primary rat brain microvascular endothelial cells (RBMVECs) were used in the uptake, efflux and transcellular transport studies. A rat bilateral in situ brain perfusion model was used to investigate the brain distribution of glabridin. The brain and tissue distribution of glabridin in rats with or without coadministered verapamil or quinidine were examined with correction for the tissue residual blood. In addition, the brain distribution of glabridin in mdr1a(-/-) mice was compared with the wild-type mice. Glabridin in various biological matrices was determined by a validated liquid chromatography mass spectrometric method.
Results. The uptake and efflux of glabridin in cultured RBMVECs were ATP-dependent and significantly altered in the presence of a PgP or multi-drug resistance protein (Mrp1/2) inhibitor (e.g. verapamil or MK-571). A polarized transport of glabridin was found in RBMVEC monolayers with
facilitated efflux from the abluminal (BL) to luminal (AP) side. Addition of a PgP or Mrp1/2 inhibitor in both luminal and abluminal sides attenuated the polarized transport across RBMVECs. In a bilateral in situ brain perfusion model, the uptake of glabridin into the cerebrum increased from 0.42 T 0.09% at 1 min to 9.27 T 1.69% (ml/100 g tissue) at 30 min and was significantly greater than that for sucrose. Coperfusion of a PgP or Mrp1/2 inhibitor significantly increased the brain distribution of glabridin by 33.6j142.9%. The rat brain levels of glabridin were only about 27% of plasma levels when corrected by tissue residual blood and it was increased to up to 44% when verapamil or quinidine was coadministered. The area under the brain concentration-time curve (AUC) of glabridin in mdr1a(-/-) mice was 6.0-fold higher than the wild-type mice.
Conclusions. These findings indicate that PgP limits the brain penetration of glabridin through the BBB and PgP may cause drug resistance to glabridin (licorice) therapy for CNS diseases and potential drugglabridin interactions. However, further studies are needed to explore the role of other drug transporters (e.g. Mrp1-4) in restricting the brain penetration of glabridin.
Language eng
DOI 10.1007/s11095-007-9297-1
Field of Research 110404 Traditional Chinese Medicine and Treatments
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2007, Springer Science + Business Media, LLC
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Document type: Journal Article
Collection: School of Medicine
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