title: Metabolism and metabolite profiles in vitro and in vivo of ospemifene in humans and preclinical species.
abstract: BACKGROUND
  Metabolite profiles of ospemifene, a novel nonsteroidal selective estrogen receptor modulator, were surveyed as part of its development.
  
  
  METHODS
  The pharmacokinetics of ospemifene and its two major, pharmacologically active metabolites 4-hydroxyospemifene and 4'-hydroxyospemifene, was elucidated in studies of volunteer humans given various doses of ospemifene and in experiments of several animal species (rat, mouse, dog, and cynomolgus monkey), which had been used either for pharmacological or toxicological studies of ospemifene. Metabolites produced in in vitro human and animal liver preparations were compared between species and with the metabolite profiles in the in vivo investigations.
  
  
  RESULTS
  Considerable interspecies differences were observed in the metabolite profiles and quantities. The major human metabolite, 4-hydroxyospemifene, was produced in substantial amounts both in vitro and in vivo in most animal species, except dog, and thus the exposure to this metabolite seems adequate in the most important toxicology species, the rat and the cynomolgus monkey. 4'-Hydroxyospemifene was equally abundant in vitro and in vivo metabolite in mice and dogs, and consequently, its contribution to the total exposure of ospemifene-related activity would be adequately covered in animal experiments. Other ospemifene metabolites were variably detected in different species, but probably they are not of consequence to pharmacology or toxicology of ospemifene.
  
  
  CONCLUSIONS
  Overall, there are quantitative and also some qualitative differences in the metabolism of ospemifene in different species. Generally, in vitro metabolite profiles were predictive for in vivo profiles. The contribution of two major hydroxyl metabolites to activity and toxicity of ospemifene is adequately covered by at least some animal species.
authors.forename: Jouko
authors.initials: J
authors.lastname: Uusitalo
authors.forename: Miia
authors.initials: M
authors.lastname: Turpeinen
authors.forename: Ari
authors.initials: A
authors.lastname: Tolonen
authors.forename: Pasi
authors.initials: P
authors.lastname: Koskimies
authors.forename: Risto
authors.initials: R
authors.lastname: Lammintausta
authors.forename: Olavi
authors.initials: O
authors.lastname: Pelkonen
mesh_terms: D000818:Animals; D004285:Dogs; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism* / Q000633:toxicity; D013045:Species Specificity; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity
chemical_list: C571818:4-hydroxyospemifene; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; C119141:Ospemifene