title: Interactions between phytochemical components of Sutherlandia frutescens and the antiretroviral, atazanavir in vitro: implications for absorption and metabolism.
abstract: OBJECTIVE
  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, L-canavanine, 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.
authors.affiliation: Division of Pharmaceutics, Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa.
authors.forename: Adrienne C
authors.initials: AC
authors.lastname: Müller
authors.forename: Srinivas
authors.initials: S
authors.lastname: Patnala
authors.forename: Olena
authors.initials: O
authors.lastname: Kis
authors.forename: Reina
authors.initials: R
authors.lastname: Bendayan
authors.forename: Isadore
authors.initials: I
authors.lastname: Kanfer
mesh_terms: D000069446:Atazanavir Sulfate; D018938:Caco-2 Cells; D002172:Canavanine / Q000494:pharmacology; D007887:Fabaceae; D006027:Glycosides / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000378:metabolism*; D006801:Humans; D007294:Inositol / Q000031:analogs & derivatives / Q000494:pharmacology; D016488:Medicine, African Traditional; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism*; D010936:Plant Extracts / Q000494:pharmacology*; D011725:Pyridines / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D006027:Glycosides; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D010936:Plant Extracts; D011725:Pyridines; D002172:Canavanine; C021730:pinitol; D007294:Inositol; D000069446:Atazanavir Sulfate; D005680:gamma-Aminobutyric Acid