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.