Effects of epigallocatechin gallate on the oral bioavailability and pharmacokinetics of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats
College of Pharmacy, Chonnam National University, Gwangju, Republic of Korea.Anti-cancer drugs (Impact Factor: 1.78). 05/2009; 20(7):584-8. DOI: 10.1097/CAD.0b013e32832d6834
The effects of epigallocatechin gallate (EGCG) on the oral bioavailability and 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) with or without epigallocatechin (0.5, 3 and 10 mg/kg) to rats. The presence of EGCG significantly altered the pharmacokinetics of orally administered tamoxifen. Compared with the oral control group (given tamoxifen alone), the area under the plasma concentration-time curve and the peak plasma concentration of tamoxifen significantly (P<0.05 for 3 mg/kg of EGCG, P<0.01 for 10 mg/kg of EGCG) increased 48.4-77.0 and 57.1-89.7%, respectively. Consequently, the absolute bioavailability of tamoxifen in the presence of EGCG (3 and 10 mg/kg) was 48.9-78.1%, which was significantly enhanced (P<0.05 for 3 mg/kg of EGCG, P<0.01 for 10 mg/kg of EGCG) compared with the oral control group (23.7%). Moreover, the relative bioavailability of tamoxifen was 1.48-1.77-fold greater than that of the control group. EGCG at a dose of 10 mg/kg significantly increased the area under the plasma concentration-time curve (P<0.05, 40.3%) of 4-hydroxytamoxifen, but the metabolite-parent ratio of 4-hydroxytamoxifen was also significantly altered (P<0.05 for 10 mg/kg of EGCG), implying that the formation of 4-hydroxytamoxifen was considerably affected by EGCG. The increase in bioavailability of tamoxifen is likely to be due to the decrease in first-pass metabolism in the intestine and liver by inhibition of P-glycoprotein and CYP3A by EGCG. The increase in oral bioavailability of tamoxifen in the presence of EGCG should be taken into consideration of potential drug interactions between tamoxifen and EGCG.
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ABSTRACT: The present investigation reports on the conditions for preparation of tamoxifen loaded PLGA nanoparticles (Tmx-NPs) for oral administration. Tmx-NPs with >85% entrapment efficiency and 165.58 ± 3.81 nm particle size were prepared and freeze dried. Freeze dried Tmx-NPs were found to be stable in various simulated GIT media (pH 1.2, pH 3.5, pH 6.8, SGF & SIF). No significant changes in characteristics of Tmx-NPs were observed after 3 months accelerated stability studies. The cell viability in C127I cells was found to be relatively lower in Tmx-NP treated cells as compared to free Tmx treated cells. CLSM imaging reveled that nanoparticles were efficiently localized into the nuclear region of C127I cells. Oral bioavailability of Tmx was increased by 3.84 and 11.19 times as compared to the free Tmx citrate and Tmx base respectively, when formulated in NPs. In vivo oral antitumor efficacy of Tmx-NPs was carried out in DMBA induced breast tumor model and tumor size was reduced up to 41.56% as compared to untreated groups which showed an increase in tumor size up to 158.66%. Finally, Tmx-NPs showed the marked reduction in hepatotoxicty when compared with free Tmx citrate as evidenced by histopathological examination of liver tissue as well as AST, ALT and MDA levels. Therefore Tmx-NPs could have the significant value for the oral chronic breast cancer therapy with reduced hepatotoxicity.Biomaterials 10/2010; 32(2):503-15. DOI:10.1016/j.biomaterials.2010.09.037 · 8.56 Impact Factor
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ABSTRACT: Tamoxifen (TAM) is useful in the chemoprevention of breast cancer, and green tea catechins, including (-)-epigallocatechin gallate (EGCG), may have similar actions. In this study, we investigated their effects, alone or in combination, on mammary carcinogenesis using breast cancer cells and preneoplastic lesions inC3H/OuJ mice. Growth inhibitory effects of EGCG and TAM on MCF-7 cells were evaluated with the anchorage-independent colony forming assay. The effects on mammary tumor carcinogenesis and preneoplastic lesions were assessed in vivo using animals treated with GTE in drinking water (1%, 0.1%), or a tamoxifen pellet (10 mg/ animal, subcutaneously inoculated) or both agents in combination (1%GTE + 10 mg TAM). The number and size of mammary tumors were measured weekly during treatment. At 48 weeks of age, mice were sacrificed for the examination of hyperplastic alveolar nodules (HAN) and argyrophilic nucleolar organizer regions (AgNOR). In the anchorage-independent growth assay, EGCG and TAM exhibited dose-dependent antiproliferative effects on MCF-7 cells. In the tumor formation assay, tumor incidences were decreased in the GTE, TAM, and GTE+TAM groups, particularly in the latter, in which no tumors developed. AgNOR counts were also significantly lower in the 1%GTE+TAM compared with the 1%GTE group, suggesting an additional anticarcinogenic effect. These data suggest that GTE and TAM, individually and in combination, have potential for chemoprevention of breast cancer.Asian Pacific journal of cancer prevention: APJCP 01/2011; 12(2):567-71. · 2.51 Impact Factor
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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 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.European Journal of Drug Metabolism and Pharmacokinetics 03/2011; 36(3):175-82. DOI:10.1007/s13318-011-0036-y · 1.56 Impact Factor
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