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Role of P-glycoprotein in Limiting the Brain Penetration of Glabridin, An Active Isoflavan from the Root of Glycyrrhiza glabra

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Abstract

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 ± 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.

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Abbreviations

ABC:

ATP-binding cassette

AP:

Luminal

AUC:

the area under the plasma concentration-time curve

BBB:

blood-brain barrier

BL:

abluminal

Cmax :

maximum plasma concentration

CNS:

central nervous system

CSF:

cerebrospinal fluid

DMSO:

dimethyl sulfoxide

EDTA:

ethylenediaminetetraacetic acid

HBSS:

Hank’s balanced salt solution

HEPES:

N-[2-hydroxyethyl] piperazine-N9-[4-butanesulfonic acid]

HPLC:

high performance liquid chromatography

K in :

in vivo BBB permeability

K m :

Michaelis-Menten constant

LC-MS:

liquid chromatography mass spectrometry

MRP (Mrp for rat):

multi-drug resistance protein

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide

P app :

permeability coefficient

PD :

passive diffusion component

PgP:

P-glycoprotein

R brain :

the amount of a drug in the brain over that in the perfusate

RBMVEC:

rat brain microvascular endothelial cells

SDS:

sodium dodecyl sulphate

\( t_{{1 \mathord{\left/ {\vphantom {1 2}} \right. \kern-\nulldelimiterspace} 2\beta }} \) :

elimination half life

Tmax :

time to achieve Cmax

TEER:

transepithelial electric resistance

(V F)B :

volume fraction of residual blood in a tissue

Vmax :

maximum velocity

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Acknowledgements

The authors appreciate the support provided by Guangdong Provincial Cardiovascular Institute (Guangzhou, China), National 973 Grand Project of China (Grant No. 2005CB523305), the Australian Institute of Chinese Medicine, Sydney, Australia (Grant Nos. R-106-00341 & R-106-00382), Singapore Cancer Syndicate Grant SCS PS0023, and the Queensland University of Technology Academic Staff Research Fund (Brisbane, Queensland, Australia).

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Authors and Affiliations

  1. Research Center of Medical Sciences, Guangdong Provincial People’s Hospital, Guangdong Provincial Cardiovascular Institute, Guangzhou, 510080, China

    Xi-Yong Yu

  2. Department of Cardiology, Guangdong Provincial People’s Hospital, Guangdong Provincial Cardiovascular Institute, 96 Dongchuan Road, Guangzhou, 510080, China

    Shu-Guang Lin

  3. Department of Biological Science and Technology, College of Bioengineering, Nanchang University, Nanchang, China

    Zhi-Wei Zhou

  4. Department of Pharmacy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Xiao Chen

  5. Department of Pharmacology and Toxicology, Australian Institute of Chinese Medicine, Sydney, New South Wales, 2118, Australia

    Jun Liang

  6. Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Xue-Qing Yu

  7. Division of Medical Sciences, Clinical Pharmacology Laboratory, National Cancer Centre, Singapore, 169610, Singapore

    Balram Chowbay

  8. School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand

    Jing-Yuan Wen

  9. School of Medicine, Deakin University, Waurn Ponds, Victoria, 3217, Australia

    Wei Duan

  10. Faculty of Science, Department of Pharmacy, National University of Singapore, Singapore, Singapore

    Eli Chan

  11. Department of Maternal Medicine, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China

    Xiao-Tian Li

  12. Department of General Surgery, The First Municipal Hospital of Guangzhou, Guangzhou, China

    Jie Cao

  13. The Chinese Medicine Research Group, Division of Chinese Medicine, RMIT University, Melbourne, Australia

    Chun-Guang Li & Charlie Changli Xue

  14. Faculty of Sciences, Division of Pharmacy, School of Life Science, Queensland University of Technology, 2 George Street, GPO Box 2434, Brisbane, Queensland, 4001, Australia

    Shu-Feng Zhou

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  1. Xi-Yong Yu
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Yu, XY., Lin, SG., Zhou, ZW. et al. Role of P-glycoprotein in Limiting the Brain Penetration of Glabridin, An Active Isoflavan from the Root of Glycyrrhiza glabra . Pharm Res 24, 1668–1690 (2007). https://doi.org/10.1007/s11095-007-9297-1

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