title: Passive Intestinal Absorption of Representative Plant Secondary Metabolites: A Physicochemical Study.
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.
authors.affiliation: School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Petit
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Ceccarelli
authors.affiliation: School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Sylvian
authors.initials: S
authors.lastname: Cretton
authors.affiliation: School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Houriet
authors.affiliation: Department of Pharmacognosy with Medicinal Plant Unit, Medical University of Lublin, Lublin, Poland.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Skalicka-Woźniak
authors.affiliation: School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Christen
authors.affiliation: School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Carrupt
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Goracci
authors.affiliation: School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Wolfender
mesh_terms: D001688:Biological Products / Q000378:metabolism*; D018938:Caco-2 Cells; D006801:Humans; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000378:metabolism*; D008567:Membranes, Artificial; D010539:Permeability; D064209:Phytochemicals / Q000378:metabolism*; D064210:Secondary Metabolism; D012995:Solubility
chemical_list: D001688:Biological Products; D008567:Membranes, Artificial; D064209:Phytochemicals