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Planta Med 2017; 83(08): 718-726
DOI: 10.1055/s-0043-101915
Pharmacokinetic Investigations
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Passive Intestinal Absorption of Representative Plant Secondary Metabolites: A Physicochemical Study

Charlotte Petit
1   School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, Geneva, Switzerland
,
Martina Ceccarelli
2   Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy
,
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
,
Krystyna Skalicka-Woźniak
3   Department of Pharmacognosy with Medicinal Plant Unit, Medical University of Lublin, Lublin, Poland
,
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
,
Laura Goracci
2   Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy
,
Jean-Luc Wolfender
1   School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, Geneva, Switzerland
› Author Affiliations
Further Information

Publication History

received 31 August 2016
revised 23 December 2016

accepted 13 January 2017

Publication Date:
13 February 2017 (online)

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Abstract

Natural products are generally ingested as part of traditional herbal decoctions or in the current diet. However, in natural product research, the bioavailability of secondary metabolites is often poorly investigated. In this work, a systematic study was carried out in order to highlight the physicochemical parameters that mainly influence the passive intestinal absorption of natural products. For this, a representative set of natural products including alkaloids, coumarins, flavonoid aglycones and glycosides, and carboxylic acids was selected and their physicochemical properties were predicted using relevant Volsurf+ descriptors. The chemical space obtained with this unbiased method was then correlated with experimental passive intestinal permeability data, which highlighted the main influence of lipophilicity, global hydrophilicity, size, and the ionisation state on passive intestinal absorption of natural products. Since the pH range encountered in the intestine is wide, the influence of the ionisation was investigated deeper experimentally. The ionisation state of weakly ionisable natural products, such as flavonoid aglycones, alkaloids, and carboxylic acids, was found to prevent the passive intestinal absorption of such natural products completely. In addition, the impact of solubility issues on passive permeability results was evaluated in cases of poorly water-soluble natural products, such as flavonoid aglycones and coumarins. The biomimetic fasted state simulated fluid-version 2 was found to improve the apparent solubility of such poorly soluble natural products without influencing their permeability behaviours. The use of such a solubilising buffer was found to be well adapted to the hexadecane membrane-parallel artificial membrane permeability assay and can circumvent the solubility issues encountered with poorly soluble natural products in such an assay.

Key words

passive intestinal absorption - natural products - secondary metabolites - pH permeability profile - solubility - FaSSIF

Supporting information

The effective passive permeability values (log Pe) and the apparent solubility values (Sapp) that have been obtained experimentally as well as the descriptors and the PCA coordinates (loadings and scores) that have been calculated by the Volsurf+ software are detailed in the Supporting Information. The compositions of the two buffers used in HDM-PAMPA (original phosphate buffer and intestino-mimetic FaSSIF-v2 buffer) are also available as Supporting Information.

 

  • References

  • 1 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
  • 2 Liu JY, Lee KF, Sze CW, Tong Y, Tang SCW, 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
  • 3 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
  • 4 Nicoletti M. Nutraceuticals and botanicals: overview and perspectives. Int J Food Sci Nutr 2012; 63: 2-6
    CrossrefPubMedGoogle Scholar
  • 5 Dillard CJ, German JB. Phytochemicals: nutraceuticals and human health. J Sci Food Agric 2000; 80: 1744-1756
    CrossrefPubMedGoogle Scholar
  • 6 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
  • 7 Chen ML, Amidon GL, Benet LZ, Lennernas H, Yu LX. The BCS, BDDCS, and regulatory guidances. Pharm Res 2011; 28: 1774-1778
    CrossrefPubMedGoogle Scholar
  • 8 Balimane PV, Han YH, Chong SH. Current industrial practices of assessing permeability and P-glycoprotein interaction. AAPS J 2006; 8: E1-E13
    CrossrefPubMedGoogle Scholar
  • 9 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
  • 10 Avdeef A. Permeability – PAMPA. In: Avdeef A. ed. Absorption and Drug Development. Solubility, Permeability and Charge State. 2nd ed.. Hoboken, New Jersey: Wiley; 2012: 319-498
    CrossrefGoogle Scholar
  • 11 Matsson P, Bergström CAS, 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
  • 12 Artursson P. Epithelial transport of drugs in cell culture. I: A model for studying the passive diffusion of drugs over intestinal absorbtive (Caco-2) cells. J Pharm Sci 1990; 79: 476-482
    CrossrefPubMedGoogle Scholar
  • 13 Avdeef A. The rise of PAMPA. Expert Opin Drug Metab Toxicol 2005; 1: 325-342
    CrossrefPubMedGoogle Scholar
  • 14 Faller B. Artificial membrane assays to assess permeability. Curr Drug Metab 2008; 9: 886-892
    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 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
  • 17 Goracci L, Buratta S, Urbanelli L, Ferrara G, Di Guida R, Emiliani C, Cross S. Evaluating the risk of phospholipidosis using a new multidisciplinary pipeline approach. Eur J Med Chem 2015; 92: 49-63
    CrossrefPubMedGoogle Scholar
  • 18 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
  • 19 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
  • 20 Petit C, Bujard A, Skalicka-Wozniak K, Cretton S, Houriet J, Christen P, Carrupt PA, Wolfender JL. Prediction of the passive intestinal absorption of medicinal plant extract constituents with the Parallel Artificial Membrane Permeability Assay (PAMPA). Planta Med 2016; 82: 424-431
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Dobson CM. Chemical space and biology. Nature 2004; 432: 824-828
    CrossrefPubMedGoogle Scholar
  • 22 Larsson J, Gottfries J, Bohlin L, Backlund A. Expanding the ChemGPS chemical space with natural products. J Nat Prod 2005; 68: 985-991
    CrossrefPubMedGoogle Scholar
  • 23 Wetzel S, Schuffenhauer A, Roggo S, Ertl P, Waldmann H. Cheminformatic analysis of natural products and their chemical space. Chimia (Aarau) 2007; 61: 355-360
    CrossrefPubMedGoogle Scholar
  • 24 John JE. Natural products-based drugs and membrane permeability, a hypothesis. Chem Biol Drug Des 2009; 73: 367-368
    CrossrefPubMedGoogle Scholar
  • 25 Cruciani G, Crivori P, Carrupt PA, Testa B. Molecular fields in quantitative structure permeation relationships: the VolSurf approach. J Mol Struct (Theochem) 2000; 503: 17-30
    CrossrefPubMedGoogle Scholar
  • 26 Jantratid E, Dressman J. Biorelevant dissolution media simulating the proximal human gastrointestinal tract: an update. Dissolut Technol 2009; 16: 21-25
    PubMedGoogle Scholar
  • 27 Galia E, Nicolaides E, Hörter D, Löbenberg R, Reppas C, Dressman JB. Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs. Pharm Res 1998; 15: 698-705
    CrossrefPubMedGoogle Scholar
  • 28 Gomes NGM, Campos MGC, Órfão JMC, Ribeiro CAF. Plants with neurobiological activity as potential targets for drug discovery. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33: 1372-1389
    CrossrefPubMedGoogle Scholar
  • 29 Milletti F, Storchi L, Sforna G, Cruciani G. New and original pKa prediction method using grid molecular interaction fields. J Chem Inf Model 2007; 47: 2172-2181
    CrossrefPubMedGoogle Scholar
  • 30 Milletti F, Storchi L, Goracci L, Bendels S, Wagner B, Kansy M, Cruciani G. Extending pKa prediction accuracy: high-throughput pKa measurements to understand pKa modulation of new chemical series. Eur J Med Chem 2010; 45: 4270-4279
    CrossrefPubMedGoogle Scholar
  • 31 Goodford PJ. A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. J Med Chem 1985; 28: 849-857
    CrossrefPubMedGoogle Scholar
  • 32 Carosati E, Sciabola S, Cruciani G. Hydrogen bonding interactions of covalently bonded fluorine atoms: from crystallographic data to a new angular function in the GRID force field. J Med Chem 2004; 47: 5114-5125
    CrossrefPubMedGoogle Scholar
  • 33 Mannhold R, Berellini G, Carosati E, Benedetti P. Use of MIF-based VolSurf Descriptors in physicochemical and pharmacokinetic Studies. In: Cruciani G. ed. Molecular Interaction Fields. Weinheim: Wiley-VCH; 2006: 173-196
    Google Scholar
  • 34 Müller C, Harir M, Hertkorn N, Kanawati B, Tziotis D, Schmitt-Kopplin P. Using ultrahigh-Resolution Mass Spectrometry to unravel the chemical Space of complex natural Product Mixtures. In: Havlícek V, Spízek J. eds. Natural Products Analysis: Instrumentation, Methods, and Applications. New Jersey: John Wiley & Sons; 2014: 545-570
    Google Scholar
  • 35 Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 1997; 23: 3-25
    CrossrefPubMedGoogle Scholar
  • 36 Bard B, Martel S, Carrupt PA. High throughput UV method for the estimation of thermodynamic solubility and the determination of the solubility in biorelevant media. Eur J Pharm Sci 2008; 33: 230-240
    CrossrefPubMedGoogle Scholar
  • 37 Westergaard H, Dietschy JM. The mechanism whereby bile acid micelles increase the rate of fatty acid and cholesterol uptake into the intestinal mucosal cell. J Clin Invest 1976; 58: 97
    CrossrefPubMedGoogle Scholar
  • 38 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
  • 39 Németh K, Plumb GW, Berrin JG, Juge N, Jacob R, Naim HY, Williamson G, Swallow DM, Kroon PA. Deglycosylation by small intestinal epithelial cell beta-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
  • 40 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
  • 41 Petit C, Bujard A, Skalicka-Wozniak K, Cretton S, Houriet J, Christen P, Carrupt PA, Wolfender JL. High-throughput prediction of passive intestinal absorption of natural products and plant extracts with the PAMPA assay. Planta Med 2015; 81: SL1A_03
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 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
  • 43 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