Tamoxifen inhibits cytochrome P450 2C9 activity: A possible mechanism for tamoxifen-warfarin interaction

Abstract

2133 Background: Cytochrome P450 2C9 (CYP2C9) is a clinically important drug metabolizing enzyme, responsible for degradation of warfarin and some other drugs such as acenocoumarol, phenytoin, losartan, oral antidiabetics, non-steroidal anti-inflammatory drugs, etc. Tamoxifen has been reported to potentiate the anticoagulant effect of warfarin, and this interaction can be life-threatening. The mechanism of this interaction has not been identified, yet. Recently, urinary losartan/E-3174 (carboxy metabolite of losartan) ratio has been suggested as a marker for CYP2C9 metabolic activity. The aim of this study was to determine the influence of tamoxifen on CYP2C9 activity. Patients & Method: Six breast cancer patients that would start tamoxifen after adjuvant chemotherapy were included. A single oral dose of 25 mg losartan was given to the patients two days before and two weeks after starting tamoxifen therapy. Losartan and E-3174 in 8-hour urine were assayed by HPLC. The ratios of losartan/E-3174 before the tamoxifen treatment were compared to those during the treatment for each patient. Results: Tamoxifen increased the urinary losartan/E-3174 ratio in five of the patients, up to 6-fold (2.8-fold ± 0.8; mean ± SEM, p=0.03). Conclusion: Tamoxifen inhibits CYP2C9 activity in breast cancer patients as assessed with losartan as a probe drug. The inhibition of CYP2C9 activity may be the possible explanation for tamoxifen-warfarin interaction. CYP2C9 inhibition by tamoxifen may also be important for other CYP2C9 substrates with low therapeutic index like acenocoumarol, phenytoin and oral antidiabetics. (Supported by a grant from the Scientific and Technical Research Council of Turkey, SBAG-COST B15 –2356) No significant financial relationships to disclose.