Abstract
Sutherlandia frutescens (Fabiacea) is traditionally used for the treatment of gastrointestinal disorders. It has recently gained popularity for its use in patients with cancer and AIDS. In the present study we investigated the ADME properties of Sutherlandioside B, a major constituent of this plant which can be used as a marker compound. A panel of in vitro assays was used to predict its gastric, intestinal and metabolic stability, intestinal transport, protein binding and interaction with CYP 3A4 and 2D6. Stability was determined in simulated gastric and intestinal fluids (SGF pH 1.2 and SIF pH 6.8). Intestinal transport was monitored in Caco-2 cell model. Metabolic stability was determined in human liver microsomes. Protein binding was measured by equilibrium dialysis. Quantitation was performed by UPLC/MS. Inhibition of CYP 3A4 and 2D6 was determined by using cDNA overexpressed enzymes and fluorescence substrates. The compound was unstable in SGF (46% degradation in 30 minutes) and stable in SIF (5% degradation in 120 minutes). A significant efflux of the compound was observed which was blocked by verapamil and MK-571 (inhibitors of MRP and Pgp). The compound was highly stable in liver microsomes (T1/2 of 495 minutes). The level of unbound drug was 50% in human plasma. The compound inhibited catalytic activity of CYP3A4 with IC50 of 20 µM, while no effect was observed on CYP2D6. It may be concluded that Sutherlandioside B is highly unstable in gastric fluids and the transport is mediated by Pgp and MRP transporters. The compound was not metabolized by liver microsomes and significant amounts were unbound to plasma proteins. A weak inhibition of CYP3A4 was observed. Acknowledgements: This work was supported in part by “The International Center for Indigenous Phytotherapy Studies” funded by NCCAM, grant number 5 U19 AT 003264 and the USDA Agricultural Research Service Specific Cooperative Agreement No. 58-6408-2-0009.
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