Effects of Ospemifene on Drug Metabolism Mediated by Cytochrome P450 Enzymes in Humans in Vitro and in Vivo

International Journal of Molecular Sciences

Miia Turpeinen²  Jouko Uusitalo¹  Terhi Lehtinen³  Marita Kailajärvi³  Olavi Pelkonen²  Jouni Vuorinen⁶  Pasi Tapanainen⁴  Camilla Stjernschantz⁵  Risto Lammintausta⁵ 

[1] Technopolis Plc, Oulu 90590, Finland; E-Mail:;Department of Pharmacology and Toxicology, University of Oulu, Oulu 90230, Finland; E-Mail:;Clinical Research Services Turku, Institute of Biomedicine, Turku 20520, Finland; E-Mails:;Vitabalans Ltd., Hämeenlinna 13500, Finland; E-Mail:;Hormos Medical Ltd., Turku 20520, Finland; E-Mails:;Pharma Ltd., Turku 20520, Finland; E-Mail:

关键词: bupropion;    CYP;    omeprazole;    selective estrogen receptor modulator;    warfarin;   

DOI  :  10.3390/ijms140714064

来源: mdpi

【 摘 要 】

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.

【 授权许可】

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© 2013 by the authors; licensee MDPI, Basel, Switzerland