Effects of ospemifene on drug metabolism mediated by cytochrome P450 enzymes in humans in vitro and in vivo

Int J Mol Sci. 2013 Jul 5;14(7):14064-75. doi: 10.3390/ijms140714064.


The objective of these investigations was to determine the possible effects of the novel selective estrogen receptor modulator, ospemifene, on cytochrome P450 (CYP)-mediated drug metabolism. Ospemifene underwent testing for possible effects on CYP enzyme activity in human liver microsomes and in isolated human hepatocytes. Based on the results obtained in vitro, three Phase 1 crossover pharmacokinetic studies were conducted in healthy postmenopausal women to assess the in vivo effects of ospemifene on CYP-mediated drug metabolism. Ospemifene and its main metabolites 4-hydroxyospemifene and 4'-hydroxyospemifene weakly inhibited a number of CYPs (CYP2B6, CYP2C9, CYP2C19, CYP2C8, and CYP2D6) in vitro. However, only CYP2C9 activity was inhibited by 4-hydroxyospemifene at clinically relevant concentrations. Induction of CYPs by ospemifene in cultured human hepatocytes was 2.4-fold or less. The in vivo studies showed that ospemifene did not have significant effects on the areas under the plasma concentration-time curves of the tested CYP substrates warfarin (CYP2C9), bupropion (CYP2B6) and omeprazole (CYP2C19), demonstrating that pretreatment with ospemifene did not alter their metabolism. Therefore, the risk that ospemifene will affect the pharmacokinetics of drugs that are substrates for CYP enzymes is low.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Anti-Ulcer Agents / pharmacology
  • Anticoagulants / pharmacology
  • Antidepressive Agents, Second-Generation / pharmacology
  • Antineoplastic Agents, Hormonal / metabolism*
  • Antineoplastic Agents, Hormonal / pharmacokinetics
  • Antineoplastic Agents, Hormonal / toxicity
  • Area Under Curve
  • Bupropion / pharmacology
  • Cells, Cultured
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism*
  • Drug Interactions
  • Female
  • Half-Life
  • Hepatocytes / cytology
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology
  • Humans
  • Microsomes, Liver / enzymology
  • Middle Aged
  • Omeprazole / pharmacology
  • Tamoxifen / analogs & derivatives*
  • Tamoxifen / chemistry
  • Tamoxifen / metabolism
  • Tamoxifen / pharmacokinetics
  • Tamoxifen / toxicity
  • Warfarin / pharmacology


  • 4-hydroxyospemifene
  • Anti-Ulcer Agents
  • Anticoagulants
  • Antidepressive Agents, Second-Generation
  • Antineoplastic Agents, Hormonal
  • Cytochrome P-450 Enzyme Inhibitors
  • Bupropion
  • Tamoxifen
  • Warfarin
  • Cytochrome P-450 Enzyme System
  • Ospemifene
  • Omeprazole