Impact of Curcumin (with or without Piperine) on the Pharmacokinetics of Tamoxifen

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 AUC_0⁻24h 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 AUC_0⁻24h 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.

Keywords: curcumin; drug interactions; pharmacokinetics; piperine; tamoxifen.

Figure 1

The major primary metabolite N-desmethyl-tamoxifen and the minor primary metabolite 4-hydroxytamoxifen are formed by N-demethylation and 4-hydroxylation of tamoxifen, through CYP3A4 and CYP2D6 metabolism, respectively. Further CYP-mediated metabolism of these metabolites results in the formation of 4-hydroxy-N-desmetyltamoxifen (endoxifen). Endoxifen is ultimately metabolized through phase II metabolism into among others endoxifen–glucoronide through UDP-glucuronyltransferases (UGTs) and also through sulfotransferase (SULT) enzymes.

Figure 2

Endoxifen and tamoxifen AUC_0–24h per individual patient per treatment phase: (a) Tamoxifen AUC_0–24h per individual patients per treatment phase. (b) endoxifen AUC_0–24h per individual patients per treatment phase. Patients with an intermediate CYP2D6 metabolism (IM) were colored blue. Patients with an extensive CYP2D6 metabolism (EM) were colored black. Poor CYP2D6 metabolizers (PM) and ultra-rapid CYP2D6 metabolizers (UR) were colored green and red, respectively; *: decrease in AUC_0–24h >25%; a total of four patients showed a >25% decrease in endoxifen AUC_0–24h and three patients in tamoxifen AUC_0–24h when tamoxifen was administered with curcumin and piperine, compared to tamoxifen monotherapy.