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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.

 

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