title: Adverse effects by artificial grapefruit seed extract products in patients on warfarin therapy.
abstract: OBJECTIVE
  Grapefruit seed extract (GSE) is promoted as a natural product with antibacterial and antiviral properties. The aim of this study was to investigate the composition of some commercially available GSE products and evaluate their effect in vitro on two cytochrome P450 enzymes, CYP2C9 and CYP3A4.
  
  
  METHODS
  A couple on lifelong treatment with warfarin and continuous regular follow-ups took some drops of a GSE product for 3 days. The female patient experienced a minor subcutaneous haematoma 3 days later, and her international normalised ratio (INR) value was 7.9. This was reported to the Swedish Medical Products Agency (MPA) as a spontaneous post-marketing report concerning adverse drug reactions/interactions. The composition of the GSE products was determined by proton and carbon-13 nuclear magnetic resonance spectroscopy (NMR). The inhibitory effect of the GSE products on the cytochrome P450 enzymes was tested in an in vitro baculosome assay.
  
  
  RESULTS
  The NMR analysis showed that all three investigated GSE products contained the synthetic preservative benzethonium chloride (BTC) in addition to glycerol and water. No authentic GSE extract was found in any of the three GSE products analysed. Furthermore, BTC was found to be a potent inhibitor of CYP3A4 and CYP2C9 activity in vitro.
  
  
  CONCLUSIONS
  Our results suggest that BTC in the GSE products is responsible for the increase in the INR value in a patient on warfarin treatment.
authors.affiliation: Laboratory Department, Medical Products Agency, Box 26, SE, 751 03, Uppsala, Sweden. ann-kristin.arvidsson@mpa.se
authors.forename: Helena
authors.initials: H
authors.lastname: Brandin
authors.forename: Olle
authors.initials: O
authors.lastname: Myrberg
authors.forename: Torgny
authors.initials: T
authors.lastname: Rundlöf
authors.forename: Ann-Kristin
authors.initials: AK
authors.lastname: Arvidsson
authors.forename: Gunilla
authors.initials: G
authors.lastname: Brenning
mesh_terms: D000925:Anticoagulants / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000008:administration & dosage / Q000737:chemistry; D001558:Benzethonium / Q000009:adverse effects* / Q000737:chemistry / Q000302:isolation & purification; D032083:Citrus paradisi; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000008:administration & dosage / Q000737:chemistry; D004347:Drug Interactions; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D010936:Plant Extracts / Q000009:adverse effects / Q000737:chemistry; D011110:Polymorphism, Genetic; D012639:Seeds; D014859:Warfarin / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D010936:Plant Extracts; D001558:Benzethonium; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human