title: 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.
abstract: 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.
authors.affiliation: School of Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Y A
authors.initials: YA
authors.lastname: Cho
authors.forename: W
authors.initials: W
authors.lastname: Lee
authors.forename: J S
authors.initials: JS
authors.lastname: Choi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003474:Curcumin / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015643:Erythromycin Ethylsuccinate; D005456:Fluorescent Dyes; D006801:Humans; D007202:Indicators and Reagents; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020112:Rhodamine 123; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018931:Antineoplastic Agents, Hormonal; D065607:Cytochrome P-450 Enzyme Inhibitors; D005456:Fluorescent Dyes; D007202:Indicators and Reagents; D013629:Tamoxifen; D015643:Erythromycin Ethylsuccinate; C016601:afimoxifene; D020112:Rhodamine 123; D003577:Cytochrome P-450 Enzyme System; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D003474:Curcumin