title: Effects of myricetin, an anticancer compound, on the bioavailability and pharmacokinetics of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats.
abstract: This study examined the effect of myricetin, an anticancer compound, on the bioavailability and pharmacokinetics of tamoxifen and its metabolite, 4-hydroxytamoxifen, in rats. The effect of myricetin on P-glycoprotein (P-gp), cytochrome P450 (CYP)3A4 and 2C9 activity was evaluated. Myricetin inhibited CYP3A4 and 2C9 activity with IC(50) values of 7.81 and 13.5 μM, respectively, and significantly inhibited P-gp activity in a concentration-dependent manner. Pharmacokinetic parameters of tamoxifen and 4-hydroxytamoxifen were determined in rats after oral (10 mg/kg) and intravenous (2 mg/kg) administration of tamoxifen in the presence and absence of myricetin (0.4, 2, and 8 mg/kg). Compared with the oral control group (given tamoxifen alone), the area under the plasma concentration-time curve (AUC(0-∞)) and the peak plasma concentration (C (max)) of tamoxifen were significantly (P < 0.05, 2 mg/kg; P < 0.01, 8 mg/kg) increased by 41.8-74.4 and 48.4-81.7%, respectively. Consequently, the absolute bioavailability (AB) of tamoxifen with myricetin (2 and 8 mg/kg) was 29.0-35.7%, which was significantly enhanced (P < 0.05 for 2 mg/kg, P < 0.01 for 8 mg/kg) compared with the oral control group (20.4%). Moreover, the relative bioavailability (RB) of tamoxifen was 1.14- to 1.74-fold greater than that of the control group. The metabolite-parent AUC ratio (MR) was significantly reduced (P < 0.05, 8 mg/kg), implying that the formation of 4-hydroxytamoxifen was considerably affected by myricetin. The enhanced bioavailability of tamoxifen might be mainly due to inhibition of the CYP3A4- and CYP2C9-mediated metabolism of tamoxifen in the small intestine and/or in the liver, and inhibition of P-gp efflux pump in the small intestine by myricetin.
authors: College of Pharmacy, Chosun University, 375 SuSuk-dong, Dong-gu, Gwangju 501-759, Republic of Korea.
authors: Cheng
authors: C
authors: Li
authors: Sung-Cil
authors: SC
authors: Lim
authors: Jin
authors: J
authors: Kim
authors: Jun-Shik
authors: JS
authors: Choi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D004347:Drug Interactions; D004965:Estrogen Antagonists / Q000493:pharmacokinetics*; D005419:Flavonoids / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012235:Rhodamines / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004965:Estrogen Antagonists; D005419:Flavonoids; D012235:Rhodamines; D013629:Tamoxifen; C016601:afimoxifene; C040015:myricetin; D003577:Cytochrome P-450 Enzyme System; C507848:CYP2C9 protein, rat; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A