Effects of silybinin on the pharmacokinetics of tamoxifen and its active metabolite, 4-hydroxytamoxifen in rats.

The effects of silybinin, an antioxidant, on the pharmacokinetics of tamoxifen and its metabolite, 4-hydroxytamoxifen, were investigated in rats. A single dose of tamoxifen was administered intravenously (2 mg/kg) and orally (10 mg/kg) without or with silybinin (0.5, 2.5 and 10 mg/kg) to rats. Silybinin significantly altered the pharmacokinetics of orally administered tamoxifen. Compared to those in 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/kg, p<0.01 for 10 mg/kg) increased by 40.2-71.3% and 45.2-78.6%, respectively, with silybinin. Consequently, the absolute bioavailability (AB) of tamoxifen in the presence of silybinin (2.5 and 10 mg/kg) was 31.1-38.1%, which was significantly enhanced (p<0.05) compared to that in the oral control group (22.2%). Moreover, the relative bioavailability (RB) of tamoxifen was 1.40- to 1.72-fold greater than that in the control group. Silybinin (10 mg/kg) significantly increased the AUC(0-infinity) (p<0.05, 40.0%) of 4-hydroxytamoxifen, but the metabolite-parent ratio (MR) of 4-hydroxytamoxifen was significantly altered (p<0.05 for 10 mg/kg), implying that the formation of 4-hydroxytamoxifen was considerably affected by silybinin. The enhanced bioavailability of tamoxifen by silybinin might be due to the promotion of intestinal absorption in the small intestine and the reduction of first-pass metabolism of tamoxifen in the small intestine and in the liver. If these results are confirmed in clinical trials, the tamoxifen dosage should be adjusted when tamoxifen is administered with silybinin or silybinin-containing dietary supplements.