Drug interaction potential of toremifene and N-desmethyltoremifene with multiple cytochrome P450 isoforms

Abstract

1. Toremifene is an effective agent for the treatment of breast cancer in postmenopausal women and is being evaluated for its ability to prevent bone fractures in men with prostate cancer taking androgen deprivation therapy.

2. Due to the potential for drug–drug interactions, the ability of toremifene and its primary circulating metabolite N-desmethyltoremifene (NDMT) to inhibit nine human cytochrome P450 (CYP) enzymes was determined using human liver microsomes. Induction of CYP1A2 and 3A4 by toremifene was also investigated in human hepatocytes.

3. Toremifene did not significantly inhibit CYP1A2 or 2D6. However, toremifene is a competitive inhibitor of CYP3A4, non-competitive inhibitor of CYP2A6, 2C8, 2C9, 2C19 and 2E1 and mixed-type inhibitor of CYP2B6. CYP inhibition by NDMT was similar in magnitude to toremifene. Toremifene did not induce CYP1A2 but increased CYP3A4 monooxygenase activity and gene expression in drug-exposed human primary hepatocytes.

4. Although clinical doses of toremifene produce steady state exposures to toremifene and NDMT that may be sufficient to cause pharmacokinetic drug–drug interactions with other drugs metabolised by CYP2B6, CYP2C8, CYP3A4, CYP2C9 and CYP2C19, these data indicate that toremifene is unlikely to play a role in clinical drug–drug interactions with substrate drugs of CYP1A2 and CYP2D6.

Keywords::

• Metabolism
• drug–drug interaction
• liver microsomes
• hepatocytes
• enzyme inhibition
• enzyme induction
• pharmacokinetics

Acknowledgements

The authors would like to thank Dr. Jeanette Hill for providing scientific input towards the experimental design and analysis of the data. In addition, the assistance of Ms. Brenda Bennett and Ms. Tamara Berry with the preparation of this manuscript is gratefully acknowledged.

Declaration of interest

J. Kim, K. A. Veverka and J. T. Dalton are employed by, and possess stock options for, GTx, Inc. C. Peraire and J. Solà are employees of Ipsen Pharma S.A. All authors involved in this study were implementing broad drug research and development activities and were not specially incentivised for this particular research or communication.