Abstract
Tamoxifen is a prodrug that is primarily metabolized into the pharmacologically active metabolite endoxifen and eventually into inactive metabolites. The herb curcumin may increase endoxifen exposure by affecting phase II metabolism. We compared endoxifen and tamoxifen exposure in breast cancer patients with or without curcumin, and with addition of the bio-enhancer piperine. Tamoxifen (20–30mg per day (q.d.)) was either given alone, or combined with curcumin (1200 mg three times daily (t.i.d.)) +/− piperine (10 mg t.i.d.). The primary endpoint of this study was the difference in geometric means for the area under the curve (AUC) of endoxifen. Genotyping was performed to determine CYP2D6 and CYP3A4 phenotypes. The endoxifen AUC0–24h decreased with 7.7% (95%CI: −15.4 to 0.7%; p = 0.07) with curcumin and 12.4% (95%CI: −21.9 to −1.9%; p = 0.02) with curcumin and piperine, compared to tamoxifen alone. Tamoxifen AUC0–24h showed similar results. For patients with an extensive CYP2D6 metabolism phenotype (EM), effects were more pronounced than for intermediate CYP2D6 metabolizers (IMs). In conclusion, the exposure to tamoxifen and endoxifen was significantly decreased by concomitant use of curcumin (+/− piperine). Therefore, co-treatment with curcumin could lower endoxifen concentrations below the threshold for efficacy (potentially 20–40% of the patients), especially in EM patients.
Highlights
Breast cancer is one of the most commonly diagnosed malignancies worldwide and one of the leading causes of cancer-related deaths in women [1]
Analysis showed no variants for CYP3A4*22. As this polymorphism is considered most relevant for CYP3A4, a predicted normal CYP3A4 phenotype for all study patients based on genotype was assumed [13,14]
This effect was even more pronounced when tamoxifen was administered with curcumin and piperine
Summary
Breast cancer is one of the most commonly diagnosed malignancies worldwide and one of the leading causes of cancer-related deaths in women [1]. Cancers 2019, 11, x receptor-positive breast cancer have been extensively treated with endocrine therapy such as tamoxifen. Tamoxifen modulator in in breast cancer tissue, thereby reducing the Tamoxifen acts actsas asaaselective selectiveestrogen estrogenreceptor receptor modulator breast cancer tissue, thereby reducing riskrisk of disease recurrence andand breast cancer-specific mortality [2]. The of disease recurrence breast cancer-specific mortality. 20–30% of all cancer patients, especially breast cancer patients, use herbal medicine besides their conventional therapy [3]. Curcumin is characterized a poor bioavailability because its supposed anti-cancer effects [4]. Curcumin is characterized by a by poor bioavailability because of its of its absorption poor absorption and rapid metabolism [5]. Curcumin is often in combination poor and rapid metabolism [5]. Curcumin is often used used in combination with with piperine (a component of black pepper)
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