title: Role of P-glycoprotein in limiting the brain penetration of glabridin, an active isoflavan from the root of Glycyrrhiza glabra.
abstract: OBJECTIVE
  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.
  
  
  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 +/- 0.09% at 1 min to 9.27 +/- 1.69% (ml/100 g tissue) at 30 min and was significantly greater than that for sucrose. Co-perfusion of a PgP or Mrp1/2 inhibitor significantly increased the brain distribution of glabridin by 33.6-142.9%. 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 drug-glabridin 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.
authors.affiliation: Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Provincial Cardiovascular Institute, Guangzhou, 510080, China. yuxycn@hotmail.com
authors.forename: Xi-Yong
authors.initials: XY
authors.lastname: Yu
authors.forename: Shu-Guang
authors.initials: SG
authors.lastname: Lin
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Zhou
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.forename: Jun
authors.initials: J
authors.lastname: Liang
authors.forename: Xue-Qing
authors.initials: XQ
authors.lastname: Yu
authors.forename: Balram
authors.initials: B
authors.lastname: Chowbay
authors.forename: Jing-Yuan
authors.initials: JY
authors.lastname: Wen
authors.forename: Wei
authors.initials: W
authors.lastname: Duan
authors.forename: Eli
authors.initials: E
authors.lastname: Chan
authors.forename: Xiao-Tian
authors.initials: XT
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Cao
authors.forename: Chun-Guang
authors.initials: CG
authors.lastname: Li
authors.forename: Charlie Changli
authors.initials: CC
authors.lastname: Xue
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhou
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D007529:Isoflavones; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability; D010636:Phenols / Q000493:pharmacokinetics* / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007529:Isoflavones; D010636:Phenols; D014700:Verapamil; C107601:glabridin; D011802:Quinidine