Abstract
In this study intestinal and blood-brain barrier (BBB) permeability of ginkgolides A, B, C, J and bilobalide, isolated from Ginkgo biloba (Ginkgoaceae), was evaluated in Caco-2 and MDR1-MDCK cell monolayer models. The transport was examined for 2 hours in both absorptive and secretory directions. Quantitation was performed by UPLC‐MS. In the Caco-2 model, each compound (100 µM) displayed a pH-dependent transport in the absorptive direction. A low permeability of ginkgolides was observed across the MDR1-MDCK model in the absorptive direction. An efflux was observed for all compounds in both the models. The efflux ratio was much higher in the MDR1-MDCK cell model (> 10) compared to the Caco-2 cell model (1.5–3.6). In comparison to ginkgolides, the permeability of bilobalide was much higher across the Caco-2 monolayer in both directions. However, a poor transport of bilobalide was observed in the MDR1-MDCK model in the absorptive direction. A high efflux was observed for all compounds in the mixture form as compared to their isolated forms. In rats, a single dose of bilobalide (8 mg/kg) administered intravenously resulted in a significant level of bilobalide in both plasma and brain. A brain-to-plasma partition coefficient of 0.56 at 120 min indicated its possibility of brain uptake.
Key words
ginkgolides - bilobalide - Ginkgoaceae - intestinal absorption - blood‐brain barrier - mass spectrometry
References
-
1
Stromgaard K, Nakanishi K.
Chemistry and biology of terpene trilactones from Ginkgo biloba.
Angew Chem Int Ed Engl.
2004;
43
1640-1658
-
2
DeKosky S T, Williamson J D, Fitzpatrick A L, Kronmal R A, Ives D G, Saxton J A, Lopez O L, Burke G, Carlson M C, Fried L P, Kuller L H, Robbins J A, Tracy R P, Woolard N F, Dunn L, Snitz B E, Nahin R L, Furberg C D.
Ginkgo biloba for prevention of dementia: a randomized controlled trial.
JAMA.
2008;
300
2253-2262
-
3
Smith J V, Luo Y.
Studies on molecular mechanisms of Ginkgo biloba extract.
Appl Microbiol Biotechnol.
2004;
64
465-472
-
4
Bedir E, Tatli I I, Khan R A, Zhao J, Takamatsu S, Walker L A, Goldman P, Khan I A.
Biologically active secondary metabolites from Ginkgo biloba.
J Agric Food Chem.
2002;
50
3150-3155
-
5
Ganzera M, Zhao J, Khan I A.
Analysis of terpenelactones in Ginkgo biloba by high performance liquid chromatography and evaporative light scattering detection.
Chem Pharm Bull (Tokyo).
2001;
49
1170-1173
-
6
Li L, Stanton J D, Tolson A H, Luo Y, Wang H.
Bioactive terpenoids and flavonoids from Ginkgo biloba extract induce the expression of hepatic drug-metabolizing enzymes through pregnane X receptor, constitutive androstane receptor, and aryl hydrocarbon receptor-mediated pathways.
Pharm Res.
2009;
26
872-882
-
7
Umegaki K, Taki Y, Endoh K, Taku K, Tanabe H, Shinozuka K, Sugiyama T.
Bilobalide in Ginkgo biloba extract is a major substance inducing hepatic CYPs.
J Pharm Pharmacol.
2007;
59
871-877
-
8
Mauri P, Simonetti P, Gardana C, Minoggio M, Morazzoni P, Bombardelli E, Pietta P.
Liquid chromatography/atmospheric pressure chemical ionization mass spectrometry of terpene lactones in plasma of volunteers dosed with Ginkgo biloba L. extracts.
Rapid Commun Mass Spectrom.
2001;
15
929-934
-
9
Mauri P, Minoggio M, Iemoli L, Rossoni G, Morazzoni P, Bombardelli E, Pietta P.
Liquid chromatography/atmospheric pressure chemical ionization ion trap mass spectrometry of terpene lactones in plasma of animals.
J Pharm Biomed Anal.
2003;
32
633-639
-
10
Biber A, Koch E.
Bioavailability of ginkgolides and bilobalide from extracts of Ginkgo biloba using GC/MS.
Planta Med.
1999;
65
192-193
-
11
Rossi R, Basilico F, Rossoni G, Riva A, Morazzoni P, Mauri P L.
Liquid chromatography/atmospheric pressure chemical ionization ion trap mass spectrometry of bilobalide in plasma and brain of rats after oral administration of its phospholipidic complex.
J Pharm Biomed Anal.
2009;
50
224-227
-
12
Lv H, Wang G, Wu X, Xie L, Huang C, Li H, Liang Y, Hao H, Sun J.
Transport characteristics of ginkgolide B by Caco-2 cells and examination of ginkgolide B oral absorption potential using rat in situ intestinal loop method.
Int J Pharm.
2008;
351
31-35
-
13
Artursson P, Borchardt R T.
Intestinal drug absorption and metabolism in cell cultures: Caco-2 and beyond.
Pharm Res.
1997;
14
1655-1658
-
14
Walgren R A, Karnaky Jr K J, Lindenmayer G E, Walle T.
Efflux of dietary flavonoid quercetin 4′-beta-glucoside across human intestinal Caco-2 cell monolayers by apical multidrug resistance-associated protein-2.
J Pharmacol Exp Ther.
2000;
294
830-836
-
15
Bohets H, Annaert P, Mannens G, Van Beijsterveldt L, Anciaux K, Verboven P, Meuldermans W, Lavrijsen K.
Strategies for absorption screening in drug discovery and development.
Curr Top Med Chem.
2001;
1
367-383
-
16
Madgula V L, Avula B, Reddy V L N, Khan I A, Khan S I.
Transport of decursin and decursinol angelate across Caco-2 and MDR-MDCK cell monolayers: in vitro models for intestinal and blood-brain barrier permeability.
Planta Med.
2007;
73
330-335
-
17
Gumbleton M, Audus K L.
Progress and limitations in the use of in vitro cell cultures to serve as permeability screen for the blood-brain barrier.
J Pharm Sci.
2001;
90
1681-1698
-
18
Wang Q, Rager J D, Weinstein K, Kardos P S, Dobson G L, Li J, Hidalgo I J.
Evaluation of the MDR-MDCK cell line as a permeability screen for the blood-brain barrier.
Int J Pharm.
2005;
288
349-359
-
19
Madgula V L, Avula B, Choi Y W, Pullela S V, Khan I A, Walker L A, Khan S I.
Transport of Schisandra chinensis extract and its biologically-active constituents across Caco-2 cell monolayers – an in-vitro model of intestinal transport.
J Pharm Pharmacol.
2008;
60
363-370
-
20
Avula B, Wang Y H, Smillie T J, Khan I A.
Column liquid chromatography/electrospray ionization-time of flight-mass spectrometry and ultraperformance column liquid chromatography/mass spectrometry methods for the determination of ginkgolides and bilobalide in the leaves of Ginkgo biloba and dietary supplements.
J AOAC Int.
2009;
92
645-652
-
21
Zuo Z, Zhang L, Zhou L, Chang Q, Chow M.
Intestinal absorption of hawthorn flavonoids – in vitro, in situ and in vivo correlations.
Life Sci.
2006;
79
2455-2462
-
22
Gutmann H, Fricker G, Torok M, Michael S, Beglinger C, Drewe J.
Evidence for different ABC-transporters in Caco-2 cells modulating drug uptake.
Pharm Res.
1999;
16
402-407
-
23
Hirohashi T, Suzuki H, Chu X Y, Tamai I, Tsuji A, Sugiyama Y.
Function and expression of multidrug resistance-associated protein family in human colon adenocarcinoma cells (Caco-2).
J Pharmacol Exp Ther.
2000;
292
265-270
-
24
Tian X, Yang X, Wang K.
The efflux of flavonoids morin, isorhamnetin-3-O-rutinoside and diosmetin-7-O-beta-D-xylopyranosyl-(1–6)-beta-D-glucopyranoside in the human intestinal cell line Caco-2.
Pharm Res.
2006;
23
1721-1728
-
25
Hilgendorf C, Ahlin G, Seithel A, Artursson P, Ungell A L, Karlsson J.
Expression of thirty-six drug transporter genes in human intestine, liver, kidney, and organotypic cell lines.
Drug Metab Dispos.
2007;
35
1333-1340
-
26
Cao J, Chen X, Liang J, Yu X Q, Xu A L, Chan E, Wei D, Huang M, Wen J Y, Yu X Y, Li X T, Sheu F S, Zhou S F.
Role of P-glycoprotein in the intestinal absorption of glabridin, an active flavonoid from the root of Glycyrrhiza glabra.
Drug Metab Dispos.
2007;
35
539-553
-
27
Garberg P, Ball M, Borg N, Cecchelli R, Fenart L, Hurst R D, Lindmark T, Mabondzo A, Nilsson J E, Raub T J, Stanimirovic D, Terasaki T, Oberg J O, Osterberg T.
In vitro models for the blood-brain barrier.
Toxicol In Vitro.
2005;
19
299-334
Shabana I. Khan
School of Pharmacy
National Center for Natural Products Research
University of Mississippi
University, MS 38677
USA
Phone: + 1 66 29 15 10 41
Fax: + 1 66 29 15 70 62
Email: skhan@olemiss.edu
