Planta Med 2017; 83(09): 790-796
DOI: 10.1055/s-0043-102494
Pharmacokinetic Investigations
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

In Vitro and In Vivo Study of the Gastrointestinal Absorption and Metabolisation of Hymenocardine, a Cyclopeptide Alkaloid

Emmy Tuenter
1   Natural Products & Food Research and Analysis (NatuRA), University of Antwerp, Antwerp, Belgium
,
Sebastiaan Bijttebier
1   Natural Products & Food Research and Analysis (NatuRA), University of Antwerp, Antwerp, Belgium
2   Flemish Institute for Technological Research (VITO), Business Unit Separation and Conversion Technology (SCT), Mol, Belgium
,
Kenn Foubert
1   Natural Products & Food Research and Analysis (NatuRA), University of Antwerp, Antwerp, Belgium
,
Annelies Breynaert
1   Natural Products & Food Research and Analysis (NatuRA), University of Antwerp, Antwerp, Belgium
,
Sandra Apers
1   Natural Products & Food Research and Analysis (NatuRA), University of Antwerp, Antwerp, Belgium
,
Nina Hermans
1   Natural Products & Food Research and Analysis (NatuRA), University of Antwerp, Antwerp, Belgium
,
Luc Pieters
1   Natural Products & Food Research and Analysis (NatuRA), University of Antwerp, Antwerp, Belgium
› Author Affiliations
Further Information

Publication History

received 23 November 2016
revised 09 January 2017

accepted 23 January 2017

Publication Date:
02 February 2017 (online)

Abstract

Hymenocardine is a cyclopeptide alkaloid present in the root bark of Hymenocardia acida. In traditional African medicine, the leaves and roots of this plant are used to treat malaria, and moderate in vitro antiplasmodial activity has been reported for hymenocardine. However, in view of its peptide-like nature, potential metabolisation after oral ingestion has to be taken into account when considering in vivo experiments. In this study, the stability and small intestinal absorption of hymenocardine was assessed using an in vitro gastrointestinal dialysis model. In addition, potential liver metabolisation was investigated in vitro by incubation with a human S9 fraction. Moreover, hymenocardine was administered to rats per os, and blood and urine samples were collected until 48 and 24 h after oral administration, respectively. All samples resulting from these three experiments were analyzed by LC-MS. Analysis of the dialysate and retentate, obtained from the gastrointestinal dialysis model, indicated that hymenocardine is absorbed unchanged from the gastrointestinal tract, at least in part. After S9 metabolisation, several metabolites of hymenocardine could be identified, the major ones being formed by the reduction and/or the loss of an N-methyl group. The in vivo study confirmed that hymenocardine is absorbed from the gastrointestinal tract unchanged, since it could be identified in both rat plasma and urine, together with hymenocardinol, its reduction product.

Supporting Information

An experimental overview (Fig. S1), the possible metabolisation reactions in hymenocardine, as predicted by Meteor and Metaprint2D-React Web Server (Fig. 2S), and an overview of the spectral and chromatographic data of hymenocardine and the metabolites formed during in vitro metabolisation with human S9 fraction (Table 1S) are available as Supporting Information. Furthermore, detailed descriptions of the methodology followed in the gastrointestinal dialysis experiment, the S9 experiment, and the analysis of plasma and urine samples are also available as Supporting Information.

 
  • References

  • 1 Tuenter E, Exarchou V, Balde A, Cos P, Maes L, Apers S, Pieters L. Cyclopeptide alkaloids from Hymenocardia acida . J Nat Prod 2016; 79: 1746-1751
  • 2 Vonthron-Senecheau C, Weniger B, Ouattara M, Bi FT, Kamenan A, Lobstein A, Brun R, Anton R. In vitro antiplasmodial activity and cytotoxicity of ethnobotanically selected Ivorian plants. J Ethnopharmacol 2003; 87: 221-225
  • 3 El-Seedi HR, Zahra MH, Goransson U, Verpoorte R. Cyclopeptide alkaloids. Phytochem Rev 2007; 6: 143-165
  • 4 Gournelis DC, Laskaris GG, Verpoorte R. Cyclopeptide alkaloids. Nat Prod Rep 1997; 14: 75-82
  • 5 Suksamrarn S, Suwannapoch N, Aunchai N, Kuno M, Ratananukul P, Haritakun R, Jansakul C, Ruchirawat S. Ziziphine N, O, P and Q, new antiplasmodial cyclopeptide alkaloids from Ziziphus oenoplia var. brunoniana . Tetrahedron 2005; 61: 1175-1180
  • 6 Tuenter E, Ahmad R, Foubert K, Amin A, Cos P, Maes L, Apers S, Pieters L, Exarchou V. Isolation and structure elucidation by LC-DAD-MS and LC-DAD-SPE-NMR of cyclopeptide alkaloids from the roots of Ziziphus oxyphylla and evaluation of their antiplasmodial activity. J Nat Prod 2016; 79: 2865-2872
  • 7 Panseeta P, Lomchoey K, Prabpai S, Kongsaeree P, Suksamrarn A, Ruchirawat S, Suksamrarn S. Antiplasmodial and antimycobacterial cyclopeptide alkaloids from the root of Ziziphus mauritiana . Phytochemistry 2011; 72: 909-915
  • 8 Han BH, Park MH, Park JH. Chemical and pharmacological studies on sedative cyclopeptide alkaloids in some Rhamnaceae plants. Pure Appl Chem 1989; 61: 443-448
  • 9 Han H, Ma Y, Eun JS, Yun SR, Kim CS, Hong JT, Oh KW. Anxiolytic-like effects of sanjoinine A isolated from Zizyphi spinosi semen: Involvement of GABA receptors. Planta Med 2008; 74: PA99
  • 10 Ma Y, Han H, Nam SY, Kim YB, Hong JT, Yun YP, Oh KW. Cyclopeptide alkaloid fraction from Zizyphi spinosi semen enhances pentobarbital-induced sleeping behaviors. J Ethnopharmacol 2008; 117: 318-324
  • 11 Suh DY, Kim YC, Kang YH, Han YN, Han BH. Metabolic cleavage of frangufoline in rodents: in vitro and in vivo study. J Nat Prod 1997; 60: 265-269
  • 12 Suh DY, Kim YC, Han YN, Han BH. Unusual enamide cleavage of frangufoline under mild acidic condition. Heterocycles 1996; 43: 2347-2351
  • 13 Maleknia SD, Johnson R. Mass Spectrometry of amino Acids and Proteins. In: Hughes AB. ed. Amino Acids, Peptides and Proteins in organic Chemistry. Weinheim: Wiley-VCH; 2011: 1-50
  • 14 Breynaert A, Bosscher D, Kahnt A, Claeys M, Cos P, Pieters L, Hermans N. Development and validation of an in vitro experimental gastrointestinal dialysis model with colon phase to study the availability and colonic metabolisation of polyphenolic compounds. Planta Med 2015; 81: 1075-1083
  • 15 Van den Eede N, Maho W, Erratico C, Neels H, Covaci A. First insights in the metabolism of phosphate flame retardants and plasticizers using human liver fractions. Toxicol Lett 2013; 223: 9-15