title: The effect of complementary and alternative medicines on CYP3A4-mediated metabolism of three different substrates: 7-benzyloxy-4-trifluoromethyl-coumarin, midazolam and docetaxel.
abstract: OBJECTIVE
  Concomitant use of complementary and alternative medicine (CAM) and anticancer drugs can affect the pharmacokinetics of anticancer drugs by inhibiting the metabolizing enzyme cytochrome P450 3A4 (CYP3A4) (EC 1.14.13.157). Several in vitro studies determined whether CAM can inhibit CYP3A4, but these studies revealed contradictory results. A plausible explanation for these conflicting results is the use only of a single model CYP3A4 substrate in each study. Therefore, the objective was to determine the potential of selected CAM (β-carotene, Echinacea, garlic, Ginkgo biloba, ginseng, grape seed extract, green tea extract, milk thistle, saw palmetto, valerian, vitamin B6, B12 and C) to inhibit CYP3A4-mediated metabolism of different substrates: 7-benzyloxy-4-trifluoromethyl-coumarin (BFC), midazolam and docetaxel. The effect of CAM on CYP3A4-mediated metabolism of an anticancer drug has never been determined before in vitro, which makes this study unique. The oncolytic CYP3A4 substrate docetaxel was used to establish the predictive value of the model substrates for pharmacokinetic interactions between CAM and anticancer drugs in vitro, and to more closely predict these interactions in vivo.
  
  
  METHODS
  The inhibition of CYP3A4-mediated metabolism of 7-benzyloxy-4-trifluoromethyl-coumarin (BFC) by CAM was assessed in Supersomes, using the fluorometric CYP3A4 inhibition assay. In human liver microsomes (HLM) the inhibition of CYP3A4-mediated metabolism of midazolam and docetaxel was determined, using liquid-chromatography coupled to tandem mass spectrometry (LC-MS/MS).
  
  
  RESULTS
  The results confirmed grape seed and green tea as potent inhibitors and milk thistle as moderate inhibitor of CYP3A4-mediated metabolism of BFC, midazolam and docetaxel.
  
  
  CONCLUSIONS
  Clinical studies are required to determine the clinical relevance of the determined CYP3A4 inhibition by grape seed, green tea and milk thistle.
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Kim D
authors.initials: KD
authors.lastname: Mooiman
authors.forename: Roel F
authors.initials: RF
authors.lastname: Maas-Bakker
authors.forename: Jeroen J M A
authors.initials: JJ
authors.lastname: Hendrikx
authors.forename: Paul C D
authors.initials: PC
authors.lastname: Bank
authors.forename: Hilde
authors.initials: H
authors.lastname: Rosing
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: D000529:Complementary Therapies; D003374:Coumarins / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000502:physiology*; D000077143:Docetaxel; D020441:Ginkgo biloba; D056604:Grape Seed Extract / Q000494:pharmacology; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D008874:Midazolam / Q000378:metabolism*; D020944:Silybum marianum; D043823:Taxoids / Q000378:metabolism*; D013662:Tea
chemical_list: C419147:7-benzyloxy-4-trifluoromethylcoumarin; D003374:Coumarins; D056604:Grape Seed Extract; D043823:Taxoids; D013662:Tea; D000077143:Docetaxel; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam
keywords: complementary and alternative medicine; cytochrome P450 3A4; docetaxel; midazolam; pharmacokinetic interactions