title: Enhanced bioavailability of tamoxifen after oral administration of tamoxifen with quercetin in rats.
abstract: Orally administered tamoxifen undergoes a first-pass metabolism and substrates for multidrug resistance (MDR) transporters efflux in the liver and intestines, which obstructs its systemic exposure. This study investigated the effect of quercetin, a dual inhibitor of CYP3A4 and P-gp, on the bioavailability and pharmacokinetics of tamoxifen and one of its metabolites, 4-hydroxytamoxifen, in rats. The pharmacokinetic parameters of tamoxifen and 4-hydroxytamoxifen in plasma were determined after orally administering tamoxifen (10 mg/kg) with or without quercetin (2.5, 7.5 and 15 mg/kg). The coadministration of quercetin (2.5 and 7.5 mg/kg) significantly (p < 0.05) increased the absorption rate constant (K(a)), peak concentration (C(max)) and the areas under the plasma concentration-time curve (AUC) of tamoxifen. The absolute bioavailability (AB%) of tamoxifen with 2.5 and 7.5 mg/kg quercetin ranged from 18.0% to 24.1%, which was significantly higher than the control group, 15.0% (p < 0.05). The relative bioavailability (RB%) of tamoxifen coadministered with quercetin was 1.20-1.61 times higher than the control group. The coadministration of quercetin caused no significant changes in the terminal half-life (t(1/2)) and the time to reach the peak concentration (T(max)) of tamoxifen. Compared with the control group, the coadministration of 7.5 mg/kg quercetin significantly (p < 0.05) increased the AUC of 4-hydroxytamoxifen. However, the metabolite ratios (MR; AUC of 4-hydroxytamoxifen to tamoxifen) were significantly lower (p < 0.05). This suggests that quercetin inhibits the both MDR transporters efflux and first-pass metabolism of tamoxifen. The enhanced bioavailability of tamoxifen as a result of its coadministration with quercetin might be due to the effect of quercetin promoting the intestinal absorption and reducing the first-pass metabolism of tamoxifen. If the results are further confirmed in the clinical trials, the tamoxifen dosage should be adjusted when tamoxifen is administered with quercetin or quercetin-containing dietary supplements in order to avoid potential drug interactions.
authors.affiliation: College of Pharmacy, Chonnam National University, Bukgu, Gwangju 500-757, Republic of Korea.
authors.forename: Sang-Chul
authors.initials: SC
authors.lastname: Shin
authors.forename: Jun-Shik
authors.initials: JS
authors.lastname: Choi
authors.forename: Xiuguo
authors.initials: X
authors.lastname: Li
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D007408:Intestinal Absorption / Q000187:drug effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D011794:Quercetin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D007527:Isoenzymes; D013629:Tamoxifen; C016601:afimoxifene; D011794:Quercetin; D051544:Cytochrome P-450 CYP3A