Interactions between Phytochemical Components of Sutherlandia Frutescens and the Antiretroviral, Atazanavir In Vitro: Implications for Absorption and Metabolism

Abstract

-Purpose. African traditional medicinal plants, such as Sutherlandia frutescens have the potential to interact pharmacokinetically with the protease inhibitor class of antiretrovirals, thereby impacting on their safety and efficacy. The effects of extracts and phytochemical components of Sutherlandia frutescens, on the in vitro absorption and metabolism of the protease inhibitor, atazanavir were thus investigated. Methods. Aqueous and methanolic extracts of Sutherlandia frutescens were prepared by freeze-drying of hot water and methanol decoctions of Sutherlandia frutescens plant material respectively, whilst crude triterpenoid glycoside and flavonol glycoside fractions were isolated by solvent extraction and subsequent column chromatography. Atazanavir was quantitated in the absence or presence of these compounds as well as commercially available purported constituents of Sutherlandia frutescens, namely, Lcanavanine, L-GABA and D-pinitol, after a one hour co-incubation in Caco-2 cell monolayers and human liver microsomes. Results. The triterpenoid and flavonol glycoside fractions were found to be present in the aqueous and methanolic extracts of Sutherlandia frutescens and were shown to contain the sutherlandiosides and sutherlandins known to be present in Sutherlandia frutescens. The aqueous extract and D-pinitol significantly reduced atazanavir accumulation by Caco-2 cells, implying a decrease in atazanavir absorption, whilst the opposite was true for the triterpenoid glycoside fraction. Both the aqueous and methanolic extracts inhibited atazanavir metabolism in human liver microsomes, whilst enhanced atazanavir metabolism was exhibited by the triterpenoid glycoside fraction. Conclusions. The extracts and phytochemical components of Sutherlandia frutescens influenced the accumulation of atazanavir by Caco-2 cells and also affected ATV metabolism in human liver microsomes. These interactions may have important implications on the absorption and metabolism and thus the overall oral bioavailability of atazanavir.

The Potential ofSutherlandia frutescensfor Herb-Drug Interaction

“…There is no information available in the literature to address this concern. A recent study on the in vitro effects of Sutherlandia on Caco-2 cell line suggests its potential to influence the absorption of atanavir (Müller et al, 2012). Therefore, the aim of the current study was to investigate the potential of the crude extracts of Sutherlandia to inhibit nine major cytochrome P450 (P450) isozymes with use of human liver microsomes (HLMs), two efflux and two uptake proteins using cell lines expressing the transporter proteins, and CYP3A4-mediated midazolam clearance in human hepatocytes.…”

Sutherlandia frutescens: The Meeting of Science and Traditional Knowledge

“…[45][46][47] In one of these studies, although l-canavanine increased the bioavailability and ultimately interaction with nevirapine in Caco-2 cells, no such effect was observed with the aqueous extract of Sutherlandia. 45 Long-term administration of S. frutescens extracts to male Sprague-Dawley rats for 5 days significantly reduced pharmacokinetic parameters (area under the curve and maximum concentration) of nevirapine.…”

“…46 The aqueous and methanolic extracts of S. frutescens, as well as the terpenoid and flavonol glycoside fractions, varied in their influence on the accumulation of atazanavir by Caco-2 cells and also its metabolism in human liver microsomes. 47 FIG. 6.…”

“…47 These herb-drug interactions may have important implications for the safety and efficacy of antiretrovirals in immunocompromised patients.…”

Effect of the African Traditional Medicine,Sutherlandia frutescens, on the Bioavailability of the Antiretroviral Protease Inhibitor, Atazanavir

“…In addition, SF is also purported to contain the non-protein amino-acid, L-canavanine, the inhibitory neurotransmitter, L-GABA, and the sugar, D-pinitol [11]. We recently conducted in vitro studies [15] which showed that aqueous extracts (10 mg/mL) of SF may have the potential to reduce ATV absorption and to inhibit ATV metabolism. A methanolic extract of SF in which less polar constituents in comparison to the aqueous extract are likely present may also inhibit ATV metabolism.…”