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Effects of myricetin, an anticancer compound, on the bioavailability and pharmacokinetics of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats

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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 IC50 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 (AUC0–∞) 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.

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Authors and Affiliations

  1. College of Pharmacy, Chosun University, 375 SuSuk-dong, Dong-gu, Gwangju, 501-759, Republic of Korea

    Cheng Li & Jun-Shik Choi

  2. College of Pharmacy, Chungbuk National University, Chungju, 361-763, Republic of Korea

    Sung-Cil Lim

  3. College of Pharmacy, Yanbian University, Jilin, China

    Cheng Li

  4. Clinical Trial Center, Chonnam National University Hospital, Gwangju, 501-759, Republic of Korea

    Jin Kim

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  1. Cheng Li
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  2. Sung-Cil Lim
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  4. Jun-Shik Choi
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Correspondence to Jun-Shik Choi.

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Li, C., Lim, SC., Kim, J. et al. Effects of myricetin, an anticancer compound, on the bioavailability and pharmacokinetics of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats. Eur J Drug Metab Pharmacokinet 36, 175–182 (2011). https://doi.org/10.1007/s13318-011-0036-y

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