Ospemifene metabolism in humans in vitro and in vivo: metabolite identification, quantitation, and CYP assignment of major hydroxylations
-
Ari Tolonen
,
Pasi Koskimies
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.
Conflict of interest statement
Authors’ conflict of interest disclosure:
The authors stated that there are no conflicts of interest regarding the publication of this article. Research funding played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
Research funding: Funding for these studies was provided by Hormos Medical Ltd. Shionogi Inc. holds exclusive rights to develop ospemifene through a licensing agreement with QuatRx Pharmaceuticals Company, of which Hormos Medical Ltd. is a subsidiary. O. Pelkonen has received departmental research funding from Hormos Medical Ltd.
Employment or leadership: R. Lammintausta and P. Koskimies are employees of Hormos Medical Ltd.
Honorarium: None declared.
References
1. Bachmann GA, Komi JO, Ospemifene Study Group. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study. Menopause 2010;17:480–6.10.1097/gme.0b013e3181c1ac01Search in Google Scholar
2. Simon JA. Efficacy and safety of daily ospemifene 60 mg for up to 1 year when used in the treatment of vulvar and vaginal atrophy in postmenopausal women. In: North American Menopause Society, Orlando, FL, USA, October 3–6, 2012.Search in Google Scholar
3. Komi J, Lankinen KS, Härkönen P, DeGregorio MW, Voipio S, Kivinen S, et al. Effects of ospemifene and raloxifene on hormonal status, lipids, genital tract, and tolerability in postmenopausal women. Menopause 2005;12:202–9.10.1097/00042192-200512020-00015Search in Google Scholar
4. Pelkonen O, Turpeinen M, Uusitalo J, Rautio A, Raunio H. Prediction of drug metabolism and interactions on the basis of in vitro investigations. Basic Clin Pharmacol Toxicol 2005;96:167–75.10.1111/j.1742-7843.2005.pto960305.xSearch in Google Scholar
5. Unkila M, Kari S, Yatkin E, Lammintausta R. Vaginal effects of ospemifene in the ovariectomized rat preclinical model of menopause. J Steroid Biochem Mol Biol, accepted for publication.Search in Google Scholar
6. Turpeinen M, Ghiciuc C, Opritoui M, Tursas L, Pelkonen O, Pasanen M. Predictive value of animal models for human cytochrome P450 (CYP)-mediated metabolism: a comparative study in vitro. Xenobiotica 2007;37:1367–77.10.1080/00498250701658312Search in Google Scholar
7. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 2013;138: 103–41.10.1016/j.pharmthera.2012.12.007Search in Google Scholar
8. Pelkonen O, Kaltiala EH, Larmi TK, Karki NT. Cytochrome P-450-linked monooxygenase system and drug-induced spectral interactions in human liver microsomes. Chem Biol Interact 1974;9:205–16.10.1016/S0009-2797(74)80005-0Search in Google Scholar
9. Bradford MM. Rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976;72:248–54.10.1016/0003-2697(76)90527-3Search in Google Scholar
10. Rostami-Hodjegan A, Tucker GT. Simulation and prediction of in vivo drug metabolism in human populations from in vitro data. Nat Rev Drug Discov 2007;6:140–8.10.1038/nrd2173Search in Google Scholar PubMed
©2013 by Walter de Gruyter Berlin Boston
Articles in the same Issue
- Masthead
- Masthead
- Editorial
- Pharmacogenomics: from cell to clinic
- Review
- Evaluation of drug-metabolizing enzyme hydroxylation phenotypes in Hispanic populations: the CEIBA cocktail
- Mini Review
- Concept of interactions between consumable substances in Ayurveda with special reference to foods and drugs
- Original Articles
- Ospemifene metabolism in humans in vitro and in vivo: metabolite identification, quantitation, and CYP assignment of major hydroxylations
- MDR-1 genotypes and quetiapine pharmacokinetics in healthy volunteers
- Biological characterization of the antiproliferative potential of Co(II) and Sn(IV) coordination compounds in human cancer cell lines: a comparative proteomic approach
- Utility of a column-switching LC/MS/MS method in cytochrome P450 inhibition assays using human liver microsomes
- Case Report
- Gastrointestinal bleeding secondary to interaction of Artemisia absinthium with warfarin
- Congress Abstracts
- Congress Abstracts*/Second ESPT Conference “Pharmacogenomics: From Cell to Clinic”
Articles in the same Issue
- Masthead
- Masthead
- Editorial
- Pharmacogenomics: from cell to clinic
- Review
- Evaluation of drug-metabolizing enzyme hydroxylation phenotypes in Hispanic populations: the CEIBA cocktail
- Mini Review
- Concept of interactions between consumable substances in Ayurveda with special reference to foods and drugs
- Original Articles
- Ospemifene metabolism in humans in vitro and in vivo: metabolite identification, quantitation, and CYP assignment of major hydroxylations
- MDR-1 genotypes and quetiapine pharmacokinetics in healthy volunteers
- Biological characterization of the antiproliferative potential of Co(II) and Sn(IV) coordination compounds in human cancer cell lines: a comparative proteomic approach
- Utility of a column-switching LC/MS/MS method in cytochrome P450 inhibition assays using human liver microsomes
- Case Report
- Gastrointestinal bleeding secondary to interaction of Artemisia absinthium with warfarin
- Congress Abstracts
- Congress Abstracts*/Second ESPT Conference “Pharmacogenomics: From Cell to Clinic”
