Download PDF
Planta Med 2016; 82(05): 424-431
DOI: 10.1055/s-0042-101247
Pharmacokinetic Investigations
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Prediction of the Passive Intestinal Absorption of Medicinal Plant Extract Constituents with the Parallel Artificial Membrane Permeability Assay (PAMPA)

Charlotte Petit
1   School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, Geneva, Switzerland
,
Alban Bujard
1   School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, Geneva, Switzerland
,
Krystyna Skalicka-Woźniak
2   Department of Pharmacognosy with Medicinal Plant Unit, Medical University of Lublin, Lublin, Poland
,
Sylvian Cretton
1   School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, Geneva, Switzerland
,
Joëlle Houriet
1   School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, Geneva, Switzerland
,
Philippe Christen
1   School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, Geneva, Switzerland
,
Pierre-Alain Carrupt
1   School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, Geneva, Switzerland
,
Jean-Luc Wolfender
1   School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, Geneva, Switzerland
› Author Affiliations
Further Information

Publication History

received 17 August 2015
revised 06 November 2015

accepted 13 December 2015

Publication Date:
12 February 2016 (online)

Also available at
   Permissions and Reprints

Abstract

At the early drug discovery stage, the high-throughput parallel artificial membrane permeability assay is one of the most frequently used in vitro models to predict transcellular passive absorption. While thousands of new chemical entities have been screened with the parallel artificial membrane permeability assay, in general, permeation properties of natural products have been scarcely evaluated. In this study, the parallel artificial membrane permeability assay through a hexadecane membrane was used to predict the passive intestinal absorption of a representative set of frequently occurring natural products. Since natural products are usually ingested for medicinal use as components of complex extracts in traditional herbal preparations or as phytopharmaceuticals, the applicability of such an assay to study the constituents directly in medicinal crude plant extracts was further investigated. Three representative crude plant extracts with different natural product compositions were chosen for this study. The first extract was composed of furanocoumarins (Angelica archangelica), the second extract included alkaloids (Waltheria indica), and the third extract contained flavonoid glycosides (Pueraria montana var. lobata). For each medicinal plant, the effective passive permeability values Pe (cm/s) of the main natural products of interest were rapidly calculated thanks to a generic ultrahigh-pressure liquid chromatography-UV detection method and because Pe calculations do not require knowing precisely the concentration of each natural product within the extracts. The original parallel artificial membrane permeability assay through a hexadecane membrane was found to keep its predictive power when applied to constituents directly in crude plant extracts provided that higher quantities of the extract were initially loaded in the assay in order to ensure suitable detection of the individual constituents of the extracts. Such an approach is thus valuable for the high-throughput, cost-effective, and early evaluation of passive intestinal absorption of active principles in medicinal plants. In phytochemical studies, obtaining effective passive permeability values of pharmacologically active natural products is important to predict if natural products showing interesting activities in vitro may have a chance to reach their target in vivo.

Key words

PAMPA - absorption - bioavailability - screening - natural products - medicinal extracts - passive intestinal absorption - in vitro methods

Supporting Information

 

  • References

  • 1 Drewry DH, Macarron R. Enhancements of screening collections to address areas of unmet medical need: an industry perspective. Curr Opin Chem Biol 2010; 14: 289-298
    CrossrefPubMedGoogle Scholar
  • 2 David B, Wolfender JL, Dias DA. The pharmaceutical industry and natural products: historical status and new trends. Phytochem Rev 2015; 14: 299-315
    CrossrefPubMedGoogle Scholar
  • 3 Queiroz EF, Wolfender JL. Innovative strategies in the search for bioactive plant constituents. In: Meyers RA, editor Encyclopedia of analytical chemistry. Chichester: John Wiley & Sons, Ltd.; 2006: 1-22
    CrossrefGoogle Scholar
  • 4 Butterweck V, Nahrstedt A. What is the best strategy for preclinical testing of botanicals? A critical perspective. Planta Med 2012; 78: 747-754
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Balimane PV, Han YH, Chong SH. Current industrial practices of assessing permeability and P-glycoprotein interaction. AAPS J 2006; 8: E1-E13
    CrossrefPubMedGoogle Scholar
  • 6 Lipinski CA. Drug-like properies and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods 2000; 44: 235-249
    CrossrefPubMedGoogle Scholar
  • 7 Wang J, Bell L. Technical challenges and recent advances of implementing comprehensive ADMET tools in drug discovery. In: Zhang D, Surapaneni S, editors ADME-Enabling technologies in drug design and development. Hoboken, New Jersey: John Wiley & Sons, Inc.; 2012: 129-159
    CrossrefGoogle Scholar
  • 8 Sugano K, Kansy M, Artursson P, Avdeef A, Bendels S, Di L, Ecker GF, Faller B, Fischer H, Gerebtzoff G, Lennernaes H, Senner F. Coexistence of passive and carrier-mediated processes in drug transport. Nat Rev Drug Discov 2010; 9: 597-614
    CrossrefPubMedGoogle Scholar
  • 9 Faller B. Artificial membrane assays to assess permeability. Curr Drug Metab 2008; 9: 886-892
    CrossrefPubMedGoogle Scholar
  • 10 Avdeef A. Permeability – PAMPA. In: Avdeef A, editor Absorption and drug development. Solubility, permeability and charge state. 2nd edition. Hoboken, New Jersey: Wiley; 2012: 319-498
    CrossrefGoogle Scholar
  • 11 Kansy M, Senner F, Gubernator K. Physicochemical high throughput screening: parallel artificial membrane permeation assay in the description of passive absorption processes. J Med Chem 1998; 41: 1007-1010
    CrossrefPubMedGoogle Scholar
  • 12 Wohnsland F, Faller B. High-throughput permeability pH profile and high-throughput alkane/water log P with artificial membranes. J Med Chem 2001; 44: 923-930
    CrossrefPubMedGoogle Scholar
  • 13 Le Bourdonnec Passeleu C. Prediction of passive blood-brain barrier permability with PAMPA: from small molecules to complex formulations [dissertation]. Geneva: University of Geneva, School of Pharmaceutical Sciences; 2013
    PubMedGoogle Scholar
  • 14 Di L, Kerns EH, Fan K, McConnell OJ, Carter GT. High throughput artificial membrane permeability assay for blood−brain barrier. Eur J Med Chem 2003; 38: 223-232
    CrossrefPubMedGoogle Scholar
  • 15 Ottaviani G, Martel S, Carrupt PA. Parallel artificial membrane permeability assay: a new membrane for the fast prediction of passive human skin permeability. J Med Chem 2006; 49: 3948-3954
    CrossrefPubMedGoogle Scholar
  • 16 Sinko B, Garrigues TM, Balogh GT, Nagy ZK, Tsinman O, Avdeef A, Takacs-Novak K. Skin−PAMPA: a new method for fast prediction of skin penetration. Eur J Pharm Sci 2012; 45: 698-707
    CrossrefPubMedGoogle Scholar
  • 17 Kerns EH, Di L, Petusky S, Farris M, Ley R, Jupp P. Combined application of parallel artificial membrane permeability assay and Caco-2 permeability assays in drug discovery. J Pharm Sci 2004; 93: 1440-1453
    CrossrefPubMedGoogle Scholar
  • 18 Könczöl A, Müller J, Földes E, Béni Z, Végh K, Kéry A, Balogh GT. Applicability of a blood−brain barrier specific artificial membrane permeability assay at the early stage of natural product-based CNS drug discovery. J Nat Prod 2013; 76: 655-663
    CrossrefPubMedGoogle Scholar
  • 19 Avdeef A. The rise of PAMPA. Expert Opin Drug Metab Toxicol 2005; 1: 325-342
    CrossrefPubMedGoogle Scholar
  • 20 Matsson P, Bergström CA, Nagahara N, Tavelin S, Norinder U, Artursson P. Exploring the role of different drug transport routes in permeability screening. J Med Chem 2005; 48: 604-613
    CrossrefPubMedGoogle Scholar
  • 21 Bujard A, Sol M, Carrupt PA, Martel S. Predicting both passive intestinal absorption and the dissociation constant toward albumin using the PAMPA technique. Eur J Pharm Sci 2014; 63: 36-44
    CrossrefPubMedGoogle Scholar
  • 22 Bujard A, Voirol H, Carrupt PA, Schappler J. Modification of a PAMPA model to predict passive gastrointestinal absorption and plasma protein binding. Eur J Pharm Sci 2015; 77: 273-278
    CrossrefPubMedGoogle Scholar
  • 23 Avdeef A, Strafford M, Block E, Balogh MP, Chambliss W, Khan I. Drug absorption in vitro model: filter-immobilized artificial membranes. Studies of the permeability properties of lactones in Piper methysticum forst. Eur J Pharm Sci 2001; 14: 271-280
    CrossrefPubMedGoogle Scholar
  • 24 Venzke D, Carvalho K, Ruani AP, Oliveira AS, Brighente IM, Micke GA, Barison A, Pizzolatti MG. PAMPA permeability, acetylcholinesterase inhibition and antioxidant activity of pyranoisoflavones from Polygala molluginifolia (polygalaceae). J Braz Chem Soc 2013; 24: 1991-1997
    PubMedGoogle Scholar
  • 25 Rastogi H, Jana S. Evaluation of physicochemical properties and intestinal permeability of six dietary polyphenols in human intestinal colon adenocarcinoma Caco-2 cells. Eur J Drug Metabol Pharmacokinet 2016; 41: 33-43
    CrossrefPubMedGoogle Scholar
  • 26 Serra H, Mendes T, Bronze MR, Simplicio AL. Prediction of intestinal absorption and metabolism of pharmacologically active flavones and flavanones. Bioorg Med Chem 2008; 16: 4009-4018
    CrossrefPubMedGoogle Scholar
  • 27 Tarrago T, Kichik N, Claasen B, Prades R, Teixido M, Giralt E. Baicalin, a prodrug able to reach the CNS, is a prolyl oligopeptidase inhibitor. Bioorg Med Chem 2008; 16: 7516-7524
    CrossrefPubMedGoogle Scholar
  • 28 Dillard CJ, German JB. Phytochemicals: nutraceuticals and human health. J Sci Food Agric 2000; 80: 1744-1756
    CrossrefPubMedGoogle Scholar
  • 29 Liu JY, Lee KF, Sze CW, Tong Y, Tang SC, Ng TB, Zhang YB. Intestinal absorption and bioavailability of traditional Chinese medicines: a review of recent experimental progress and implication for quality control. J Pharm Pharmacol 2013; 65: 621-633
    CrossrefPubMedGoogle Scholar
  • 30 Gertsch J. Botanical drugs, synergy, and network pharmacology: forth and back to intelligent mixtures. Planta Med 2011; 77: 1086-1098
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Nicoletti M. Nutraceuticals and botanicals: overview and perspectives. Int J Food Sci Nutr 2012; 63: 2-6
    CrossrefPubMedGoogle Scholar
  • 32 Schemann M, Michel K, Zeller F, Hohenester B, Rühl A. Region-specific effects of STW 5 (Iberogast®) and its components in gastric fundus, corpus and antrum. Phytomedicine 2006; 13 (Suppl. 05) 90-99
    CrossrefPubMedGoogle Scholar
  • 33 Cretton S, Breant L, Pourrez L, Ambuehl C, Marcourt L, Ebrahimi SN, Hamburger M, Perozzo R, Karimou S, Kaiser M, Cuendet M, Christen P. Antitrypanosomal quinoline alkaloids from the roots of Waltheria indica . J Nat Prod 2014; 77: 2304-2311
    CrossrefPubMedGoogle Scholar
  • 34 Cretton S, Bréant L, Pourrez L, Ambuehl C, Perozzo R, Marcourt L, Kaiser M, Cuendet M, Christen P. Chemical constituents from Waltheria indica exert in vitro activity against Trypanosoma brucei and T. cruzi . Fitoterapia 2015; 105: 55-60
    CrossrefPubMedGoogle Scholar
  • 35 Zhang Z, Lam TN, Zuo Z. Radix Puerariae: an overview of its chemistry, pharmacology, pharmacokinetics, and cinical use. J Clin Pharmacol 2013; 53: 787-811
    PubMedGoogle Scholar
  • 36 Avdeef A, Bendels S, Di L, Faller B, Kansy M, Sugano K, Yamauchi Y. PAMPA – critical factors for better predictions of absorption. J Pharm Sci 2007; 96: 2893-2909
    CrossrefPubMedGoogle Scholar
  • 37 Eugster P, Wolfender JL. UHPLC in natural products analysis. In: Guillarme D, Veuthey JL, editors UHPLC in life sciences. Cambridge: Royal Society of Chemistry; 2012: 357-391
    CrossrefGoogle Scholar
  • 38 Eugster P, Guillarme D, Rudaz S, Veuthey JL, Carrupt PA, Wolfender JL. Ultra high pressure liquid chromatography for crude plant extract profiling. J AOAC Int 2011; 94: 51-70
    PubMedGoogle Scholar
  • 39 Scalbert A, Williamson G. Dietary intake and bioavailability of polyphenols. J Nutr 2000; 130: 2073S-2085S
    CrossrefPubMedGoogle Scholar
  • 40 Manach C, Williamson G, Morand C, Scalbert A, Remesy C. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr 2005; 81: 230S-242S
    CrossrefPubMedGoogle Scholar
  • 41 Passamonti S, Terdoslavich M, Franca R, Vanzo A, Tramer F, Braidot E, Petrussa E, Vianello A. Bioavailability of flavonoids: a review of their membrane transport and the function of bilitranslocase in animal and plant organisms. Curr Drug Metab 2009; 10: 369-394
    CrossrefPubMedGoogle Scholar
  • 42 Németh K, Plumb GW, Berrin JG, Juge N, Jacob R, Naim HY, Williamson G, Swallow DM, Kroon PA. Deglycosylation by small intestinal epithelial cell β-glucosidases is a critical step in the absorption and metabolism of dietary flavonoid glycosides in humans. Eur J Nutr 2003; 42: 29-42
    CrossrefPubMedGoogle Scholar
  • 43 Skalicka-Wozniak K, Glowniak K. Pressurized liquid extraction of coumarins from fruits of Heracleum leskowii with application of solvents with different polarity under increasing temperature. Molecules 2012; 17: 4133-4141
    CrossrefPubMedGoogle Scholar
  • 44 Waksmundzka-Hajnos M, Petruczynik A, Dragan A, Wianowska D, Dawidowicz AL. Effect of extraction method on the yield of furanocoumarins from fruits of Archangelica officinalis Hoffm. Phytochem Anal 2004; 15: 313-319
    CrossrefPubMedGoogle Scholar
  • 45 Walasek M, Grzegorczyk A, Malm A, Skalicka-Wozniak K. Bioactivity-guided isolation of antimicrobial coumarins from Heracleum mantegazzianum Sommier & Levier (Apiaceae) fruits by high-performance counter-current chromatography. Food Chem 2015; 186: 133-138
    CrossrefPubMedGoogle Scholar
  • 46 Li B, Zhang X, Wang J, Zhang L, Gao B, Shi S, Wang X, Li J, Tu P. Simultaneous characterisation of fifty coumarins from the roots of Angelica dahurica by off-line two-dimensional high-performance liquid chromatography coupled with electrospray ionisation tandem mass spectrometry. Phytochem Anal 2014; 25: 229-240
    CrossrefPubMedGoogle Scholar
  • 47 Liu M, Shi X, Yang W, Liu S, Wang N, Shi R, Qiao S, Wang Q, Wang Y. Quantitative analysis of nine coumarins in rat urine and bile after oral administration of Radix Glehniae extract by high-performance liquid chromatography−electrospray ionization tandem mass spectrometry. Biomed Chromatogr 2011; 25: 783-793
    CrossrefPubMedGoogle Scholar
  • 48 Prasain JK, Jones K, Brissie N, Moore R, Wyss JM, Barnes S. Identification of puerarin and its metabolites in rats by liquid chromatography−tandem mass spectrometry. J Agric Food Chem 2004; 52: 3708-3712
    CrossrefPubMedGoogle Scholar
  • 49 Prasain JK, Peng N, Moore R, Arabshahi A, Barnes S, Wyss JM. Tissue distribution of puerarin and its conjugated metabolites in rats assessed by liquid chromatography tandem mass spectrometry. Phytomedicine 2009; 16: 65-71
    CrossrefPubMedGoogle Scholar
  • 50 Martel S, Guillarme D, Henchoz Y, Galland A, Veuthey JL, Rudaz S, Carrupt PA. Chromatographic approaches for measuring log P. In: Mannhold R, editor Drug properties: measurement and computation. Weinheim: Wiley-VCH; 2008: 331-356
    Google Scholar
  • 51 Martel S, Gillerat F, Carosati E, Maiarelli D, Tetko IV, Mannhold R, Carrupt PA. Large, chemically diverse dataset of logP measurements for benchmarking studies. Eur J Pharm Sci 2013; 48: 21-29
    CrossrefPubMedGoogle Scholar
  • 52 Balimane PV, Pace E, Chong S, Zhu MS, Jemal M, Van Pelt CK. A novel high-throughput automated chip-based nanoelectrospray tandem mass spectrometric method for PAMPA sample analysis. J Pharm Biomed Anal 2005; 39: 8-16
    CrossrefPubMedGoogle Scholar
  • 53 Mensch J, Noppe M, Adriaensen J, Melis A, Mackie C, Augustijns P, Brewster ME. Novel generic UPLC/MS/MS method for high throughput analysis applied to permeability assessment in early Drug Discovery. J Chromatogr B Analyt Technol Biomed Life Sci 2007; 847: 182-187
    CrossrefPubMedGoogle Scholar
  • 54 Balimane PV, Chong S. Cell culture-based models for intestinal permeability: a critique. Drug Discov Today 2005; 10: 335-343
    CrossrefPubMedGoogle Scholar