title: Ospemifene metabolism in humans in vitro and in vivo: metabolite identification, quantitation, and CYP assignment of major hydroxylations.
abstract: BACKGROUND
  The metabolism of ospemifene, a novel nonsteroidal selective estrogen receptor modulator, was investigated as part of its development.
  
  
  METHODS
  Metabolite identification, tentative quantitation, and CYP assignment of ospemifene were performed in human liver microsomes or homogenate incubations and in plasma samples from volunteer humans. The potential contributions of CYP enzymes were determined by recombinant human CYPs. Metabolite identification and tentative quantification were performed by liquid chromatography-mass spectrometry.
  
  
  RESULTS
  The relative abundances of metabolites produced were dependent on ospemifene concentration and liver preparation, but the largest quantities of 4- and 4'-hydroxy-ospemifene (and their glucuronides in smaller quantities) were produced in human liver microsomes at low ospemifene concentrations. Other metabolites were detected in in vitro incubation with human liver including a direct glucuronide of ospemifene and some metabolites with only minor abundance. In human plasma samples, 4-hydroxy-ospemifene was the most abundant metabolite, representing about 25% of the abundance of the parent compound. All the other metabolites detected in plasma, including 4'-hydroxy-ospemifene, represented <7% of the abundance of ospemifene. Several CYP enzymes participated in 4-hydroxylation, including CYP2C9, CYP2C19, CYP2B6, and CYP3A4, whereas CYP3A enzymes were the only ones to catalyze 4'-hydroxylation.
  
  
  CONCLUSIONS
  In vitro incubations with liver preparations provided a rather reliable starting point in the search for potential metabolites in clinical settings. The in vitro metabolite profile is informative for the in vivo metabolite profile, especially regarding the major hydroxylated metabolites. However, it is anticipated that extended in vivo exposures may result in an increased production of more distal metabolites from major metabolites.
authors.forename: Ari
authors.initials: A
authors.lastname: Tolonen
authors.forename: Pasi
authors.initials: P
authors.lastname: Koskimies
authors.forename: Miia
authors.initials: M
authors.lastname: Turpeinen
authors.forename: Jouko
authors.initials: J
authors.lastname: Uusitalo
authors.forename: Risto
authors.initials: R
authors.lastname: Lammintausta
authors.forename: Olavi
authors.initials: O
authors.lastname: Pelkonen
mesh_terms: D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000737:chemistry / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; D011994:Recombinant Proteins; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D003577:Cytochrome P-450 Enzyme System; C119141:Ospemifene