In vitro and in vivo study of the absorption and gastrointestinal and hepatic biotransformation of the cyclopeptide alkaloid hymenocardine

Hymenocardine is a cyclopeptide alkaloid present in the root bark of Hymenocardia acida Tul. (Phyllanthaceae). 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.[1] However, in view of its peptide-like nature, potential biotransformation after oral ingestion has to be taken into account when considering in vivo experiments. In this study, the gastric and small intestinal stability of hymenocardine was assessed using an in vitro gastrointestinal model (GIM).[2] In addition, potential biotransformation in the liver was investigated in vitro by incubation of hymenocardine with a human S9 fraction. Moreover, hymenocardine was administered to rats per os, and blood and urine samples were collected until 48h and 24h after administration, respectively. All samples resulting from these three experiments were analyzed by liquid chromatography-high resolution mass spectrometry (LC-HRMS). Analysis of the fractions obtained from the GIM indicated that hymenocardine is stable in the stomach and small intestine, in spite of its peptide-like nature. The in vitro S9 biotransformation experiment resulted in the identification of several hymenocardine metabolites, the major ones being formed by the reduction and/or the loss of an N-methyl group. The in vivo study showed that hymenocardine is absorbed unchanged from the gastrointestinal tract, since it could be identified in both rat plasma and urine, together with hymenocardinol, its reduction product (Figure).

[1] Tuenter E, Exarchou V, Baldé A, Cos P, Maes L, Apers S, Pieters L. J Nat Prod 2016; 79: 1746 – 1751

[2] Breynaert A, Bosscher D, Kahnt A, Claeys M, Cos P, Pieters L, Hermans N. Planta Med 2015; 81: 1075 – 1083

[3] Tuenter E, Bijttebier S, Foubert K, Breynaert A, Apers S, Hermans N, Pieters L. Planta Med; published online (DOI: 10.1055/s-0043 – 102494)