title: The in-vitro effect of complementary and alternative medicines on cytochrome P450 2C9 activity.
abstract: OBJECTIVE
  The aim of this study is to establish the inhibitory effects of 14 commonly used complementary and alternative medicines (CAM) on the metabolism of cytochrome P450 2C9 (CYP2C9) substrates 7-methoxy-4-trifluoromethyl coumarine (MFC) and tolbutamide. CYP2C9 is important for the metabolism of numerous drugs and inhibition of this enzyme by CAM could result in elevated plasma levels of drugs that are CYP2C9 substrates. Especially for anticancer drugs, which have a narrow therapeutic window, small changes in their plasma levels could easily result in clinically relevant toxicities.
  
  
  METHODS
  The effects of CAM on CYP2C9-mediated metabolism of MFC were assessed in Supersomes, using the fluorometric CYP2C9 inhibition assay. In human liver microsomes (HLM) the inhibition of CYP2C9-mediated metabolism of tolbutamide was determined, using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS).
  
  
  RESULTS
  The results indicated milk thistle as the most potent CYP2C9 inhibitor. For milk thistle, silybin (main constituent of milk thistle) was mainly responsible for the inhibition of CY2C9.
  
  
  CONCLUSIONS
  Milk thistle and green tea were confirmed as potent inhibitors of CYP2C9-mediated metabolism of multiple substrates in vitro. Clinical studies with milk thistle are recommended to establish the clinical relevance of the demonstrated CYP2C9 inhibition.
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.
authors.forename: Kim D
authors.initials: KD
authors.lastname: Mooiman
authors.forename: Andrew K L
authors.initials: AK
authors.lastname: Goey
authors.forename: Tomy J
authors.initials: TJ
authors.lastname: Huijbregts
authors.forename: Roel F
authors.initials: RF
authors.lastname: Maas-Bakker
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Irma
authors.initials: I
authors.lastname: Meijerman
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D028241:Camellia sinensis; D000529:Complementary Therapies; D003374:Coumarins / Q000378:metabolism*; D041743:Herb-Drug Interactions; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects; D020944:Silybum marianum / Q000737:chemistry*; D010936:Plant Extracts / Q000494:pharmacology*; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology; D014044:Tolbutamide / Q000378:metabolism*
chemical_list: C540005:7-methoxy-4-trifluoromethylcoumarin; D003374:Coumarins; D010936:Plant Extracts; D012838:Silymarin; D000077385:Silybin; D014044:Tolbutamide; D001189:Aryl Hydrocarbon Hydroxylases
keywords: 7-benzyloxy-4-trifluoromethyl coumarin; complementary and alternative medicine; cytochrome P450 2C9; pharmacokinetic interactions; tolbutamide