pgp - publications

Predict more pgp - ligand interactions now!


1. Pharmazie. 2012 Feb;67(2):124-30.

Effects of curcumin on the pharmacokinetics of tamoxifen and its active
metabolite, 4-hydroxytamoxifen, in rats: possible role of CYP3A4 and
P-glycoprotein inhibition by curcumin.

Cho YA, Lee W, Choi JS.

School of Medicine, Research Institute of Life Science, Gyeongsang National
University, Jinju, Republic of Korea.

The effects of curcumin, a natural anti-cancer compound, on the bioavailability
and pharmacokinetics of tamoxifen and its metabolite, 4-hydroxytamoxifen, were
investigated in rats. Tamoxifen and curcumin interact with cytochrom P450 (CYP)
enzymes and P-glycoprotein, and the increase in the use of health supplements may
result in curcumin being taken concomitantly with tamoxifen as a combination
therapy to treat or prevent cancer. A single dose of tamoxifen was administered
orally (9 mg x kg(-1)) with or without curcumin (0.5, 2.5 and 10 mg x kg(-1)) and
intravenously (2mg x kg(-1)) with or without curcumin (2.5 and 10 mg x kg(-1)) to
rats. The effects of curcumin on P-glycoprotein (P-gp) and CYP3A4 activity were
also evaluated. Curcumin inhibited CYP3A4 activity with 50% inhibition
concentration (IC50) values of 2.7 microM. In addition, curcumin significantly (P
< 0.01 at 10 microM) enhanced the cellular accumulation of rhodamine-123 in
MCF-7/ADR cells overexpressing P-gp in a concentration-dependent manner. This
result suggested that curcumin significantly inhibited P-gp activity. Compared to
the oral control group (given tamoxifen alone), the area under the plasma
concentration-time curve (AUC(0-infinity)) and the peak plasma concentration
(C(max)) of tamoxifen were significantly (P < 0.05 for 2.5 mg x kg(-1); P < 0.01
for 10 mg x kg(-1)) increased by 33.1-64.0% and 38.9-70.6%, respectively, by
curcumin. Consequently, the absolute bioavailability of tamoxifen in the presence
of curcumin (2.5 and 10 mg x kg(-1)) was 27.2-33.5%, which was significantly
enhanced (P < 0.05 for 2.5 mg x kg(-1); P < 0.01 for 10 mg x kg(-1)) compared to
that in the oral control group (20.4%). Moreover, the relative bioavailability of
tamoxifen was 1.12- to 1.64-fold greater than that in the control group.
Furthermore, concurrent use of curcumin significantly decreased (P < 0.05 for 10
mg x kg(-1)) the metabolite-parent AUC ratio (MR), implying that curcumin may
inhibit the CYP-mediated metabolism of tamoxifen to its active metabolite,
4-hydroxytamoxifen. The enhanced bioavailability of tamoxifen by curcumin may be
mainly due to inhibition of the CYP3A4-mediated metabolism of tamoxifen in the
small intestine and/or in the liver and to inhibition of the P-gp efflux
transporter in the small intestine rather than to reduction of renal elimination
of tamoxifen, suggesting that curcumin may reduce the first-pass metabolism of
tamoxifen in the small intestine and/or in the liver by inhibition of P-gp or
CYP3A4 subfamily.

PMID: 22512082 [PubMed - in process]