Drug/natural product interactions at the blood brain barrier
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1
Ruprecht-Karls-University, Institute of Pharmacy and Molecular Biotechnology, Germany
The use of herbal medicines is rapidly growing as most people consider them as being of natural origin and therefore being safe. More than 35,000 plant species are currently applied in medical indications [1] and the worldwide market of herbal medicines is in the order of $60 billion to $80 billion. In addition herbal or fungal constituents are also part of many standard prescription drugs, e.g. most cytostatics and antibiotics are of natural origin. Estimates say that more than 15% of all patients combine herbal remedies with prescription medications and there is a growing concern for interactions of drugs with herbal remedies or single compounds originating from plants. More than 100.000 fatalities per year in the United States can be assigned to drug interactions, placing them at the sixth cause of death [2] and larger portion of these interactions may be associated to the use of herbal products. Several of the top ten selling over the-counter herbal medicines in the United States including St John’s wort, garlic, ginkgo, echinacea, ginseng, kava and others [3], modulate the activity of drugmetabolizing enzymes, particularly cytochrome P450 isozymes, and/or drug transport proteins. Both metabolic interactions as well as interactions with transport proteins are reason of rising concern.
Of particular interest for interactions is the blood brain barrier (BBB) separating blood circulation and CNS and protecting the brain from potentially toxic metabolites and xenobiotics. However, only very few data are available on the action of natural compounds at the BBB. There, natural products and standard drugs may act at two levels: a) signaling cascades of transport proteins and enzymes may be affected resulting in an up- or down-regulation of transport and metabolism; b) natural compounds may directly inhibit or compete for transport by carrier proteins or enzymes within the BBB.
A very well studied example for a high modulatory potential is St. John´s wort (SJW), a widely used herbal antidepressant, the constituents of which directly affect transporter expression and function in the BBB. Our recent study with cultured brain capillary endothelial cells and freshly isolated brain capillaries showed that short time exposure to SJW extract and its constituents hyperforin, hypericin, and quercetin decreased P-glycoprotein (Abcb1) transport activity in a dose- and time-dependent manner (Fig 1). The data indicate that SJW extract and hyperforin directly inhibit P-glycoprotein activity, whereas the SJW constituents hypericin and quercetin appear to modulate the transporter function through a mechanism involving protein kinase C.
In addition, hyperforin, activates the orphan receptor PXR in the blood brain barrier resulting in an induction of P-glycoprotein (abcb1), which may affect pharmacokinetics/pharmacodynamics of coadministered drugs [4]. PXR is crucial in controlling drug efflux transporters, and therefore this observation may have important clinical implications for the treatment of CNS disorders.
Most of cytostatic drugs are in fact natural products or semisynthetic derivatives thereof. E.g., anthracyclines (Doxorubicin, Daunorubicin, Epirubicin, Idarubicin, Mitoxantrone, Amsacrin, Dixiflruidin) or the antibiotic agents (Bleomycin, Actinomycin D, Mitomycin) originate from Streptomyces, vinca alkaloids (Vinorelbin, Vincristin, Vinblastin, Vindesin) are derived from the Madagascar periwinkle, Taxanes (Paclitaxel, Docetaxel) from the Taxus baccata and Taxus brevifolia, topomerase inhibitors (Camptothecin, Topotecane, Irinotecane, Etoposide, Teniposide) from the Chinese plants Camptothecae. However, their use in treatment of brain tumors, especially high grade glioblastoma, has been extremely disappointing, which can at least partially be attributed to the fact that they are good substrates of the ABC-transport proteins in the blood brain barrier. In addition, it appears that some cytostatic drugs including taxanes are also able to activate PXR.
Therapeutic relevance of concomitant p-gp inhibition at the blood brain barrier was proven for the treatment of nude mice with implanted intracerebral human U-118 MG glioblastoma with paclitaxel (Figure 2). Administration of paclitaxel alone did not affect tumor volume, but co-administration of paclitaxel (intravenous) and the P-gp blocker Valspodar (PSC833; peroral) resulted in a dramatic reduction for brain tumor volume by 90% [5].
Another prime example for a direct impact on BBB function is the immune-suppressant Cyclosporine A (CSA) from fungus Tolypocladium inflatum (Gams). E.g., PET studies with mice and human volunteers demonstrated significantly higher permeation of labeled Verapamil across the BBB after CSA treatment [6,7], which can also be interpreted as an inhibition of export proteins at the BBB.
Digoxin, a cardiac glycoside from the leaves of the foxglove plant Digitalis lanata, is often used as a model compound for transport studies as it shows a relatively slow metabolism in mice. It has previously been shown that Digoxin concentrations in brains of Mdr1-knockout mice were elevated 35-fold compared to that of wild-type animals. This might be of clinical relevance with respect to CNS side effects observed under digoxin therapy. The impact of p-glycoprotein on cerebral disposition of digoxin was also demonstrated in a study showing that coadministration of the pharmaceutical excipient Pluronic P85 increased brain penetration of digoxin 3-fold, which was attributed to an inhibition of pglycoprotein mediated efflux at the BBB by the pluronic block copolymer [8].
These examples show that particular care has to be taken with respect to effects of natural compounds at the level of export proteins, which are of outstanding importance for the protective function of the BBB. Considering the rapidly increasing number of herbal preparations coming into the market, it has to be kept in mind that many herbal products are not subject to a stringent approval process. Unlike conventional drugs, most herbal products are not regulated for purity or content, and therefore, unknown contaminants or by-products me be part of the herbal preparation resulting in unwanted side effects or interactions with other drugs.
References
1. Lewington A. Medicinal Plant and Plant Extracts: A Review of Their Importation into Europe. Cambridge, UK; Traffic International. 1993.
2. Lazarou J., Pomeranz B.H., Corey F.N. Incidence of adverse drug reactions in hospitalized patients: a metaanalysis of prospective studies. JAMA 279: 1200-1205, 1999
3. Sparreboom A., Cox M.C., Acharya M.A.; Figg, W.D. Herbal remedies in the United States: Potential adverse interactions with anticancer agents. J. Clin. Oncol 22: 2489-2503, 2004
4. Ott M., Fricker G., Bauer B. Pregnane X Receptor (PXR) Regulates P-Glycoprotein at the Blood-Brain Barrier: Functional Similarities between Pig and Human PXR. J. Pharmacol. Exp. Ther. 329: 141–149, 2009
5. Fellner S., Bauer B., Miller DS., Schaffrik M., Fankhänel M., Spruß T., Bernhardt G., Graeff C., Färber L., Gschaidhammer H., Buschauer A., Fricker G.: Transport of Paclitaxel (Taxol) across the blood brain barrier in vitro and in vivo. J. Clin. Invest. 110, 1309-1318, 2002
6. Syvänen S. Blomquist G. Sprycha M, Höglund U., Roman M., Eriksson O., Hammarlund-Udenaes M., Långström B. , Bergström M.: Duration and degree of cyclosporin induced P-glycoprotein inhibition in the rat blood–brain barrier can be studied with PET. Neuroimage. 32:1134-41, 2006
7. Muzi M, Mankoff DA, Link JM, Shoner S, Collier AC, Sasongko L, Unadkat JD. Imaging of cyclosporine inhibition of P-glycoprotein activity using 11C-verapamil in the brain: studies of healthy humans. J Nucl Med. 50:1267-1275, 2009
8. Batrakova EV, Miller DW, Li S, Alakhov VY, Kabanov AV, Elmquist WF. Pluronic P85 enhances the delivery of digoxin to the brain: in vitro and in vivo studies. J Pharmacol Exp Ther. 296:551-557, 2001.
Conference:
Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU, Brussels, Belgium, 11 Feb - 12 Feb, 2010.
Presentation Type:
Oral Presentation
Topic:
Presentations
Citation:
Fricker
G,
Ott
M and
Reichel
V
(2010). Drug/natural product interactions at the blood brain barrier.
Front. Pharmacol.
Conference Abstract:
Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU.
doi: 10.3389/conf.fphar.2010.02.00013
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Received:
25 Feb 2010;
Published Online:
25 Feb 2010.
*
Correspondence:
Gert Fricker, Ruprecht-Karls-University, Institute of Pharmacy and Molecular Biotechnology, Heidelberg, Germany, gert.fricker@uni-hd.de