Metabolism and metabolite profiles in vitro and in vivo of ospemifene in humans and preclinical species
-
Jouko Uusitalo
,
Risto Lammintausta
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.
References
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©2016 by De Gruyter
Articles in the same Issue
- Frontmatter
- Editorial
- The role of pharmacogenetics and pharmacogenomics in 21st-century medicine: state of the art and new challenges discussed in the VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society (SEFF)
- Mini Reviews
- Human genetics: international projects and personalized medicine
- Clinical implementation of pharmacogenetics
- Progress in pharmacogenetics: consortiums and new strategies
- Pharmacogenetics and pharmacogenomics as tools in cancer therapy
- Original Articles
- Metabolism and metabolite profiles in vitro and in vivo of ospemifene in humans and preclinical species
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- Garlic capsule and selenium-vitamins ACE combination therapy modulate key antioxidant proteins and cellular adenosine triphosphate in lisinopril-induced lung damage in rats
- Case Report
- Severe verapamil intoxication despite correct use of low-dose verapamil
- Congress Abstracts
- VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society (SEFF). “The role of pharmacogenetics and pharmacogenomics in the XXI century medicine: current state of the art and new challenges”
Articles in the same Issue
- Frontmatter
- Editorial
- The role of pharmacogenetics and pharmacogenomics in 21st-century medicine: state of the art and new challenges discussed in the VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society (SEFF)
- Mini Reviews
- Human genetics: international projects and personalized medicine
- Clinical implementation of pharmacogenetics
- Progress in pharmacogenetics: consortiums and new strategies
- Pharmacogenetics and pharmacogenomics as tools in cancer therapy
- Original Articles
- Metabolism and metabolite profiles in vitro and in vivo of ospemifene in humans and preclinical species
- Involvement of MTHFR and TPMT genes in susceptibility to childhood acute lymphoblastic leukemia (ALL) in Mexicans
- Garlic capsule and selenium-vitamins ACE combination therapy modulate key antioxidant proteins and cellular adenosine triphosphate in lisinopril-induced lung damage in rats
- Case Report
- Severe verapamil intoxication despite correct use of low-dose verapamil
- Congress Abstracts
- VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society (SEFF). “The role of pharmacogenetics and pharmacogenomics in the XXI century medicine: current state of the art and new challenges”
