Advertisement

Archives of Pharmacal Research

, Volume 34, Issue 11, pp 1965–1972 | Cite as

Effects of baicalein on the pharmacokinetics of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats: Possible role of cytochrome p450 3A4 and P-glycoprotein inhibition by baicalein

  • Cheng Li
  • Minhee Kim
  • HongSeok Choi
  • JunShik ChoiEmail author
Research Articles Drug Development

Abstract

The purpose of this study was to investigate the effects of baicalein on the pharmacokinetics of tamoxifen and its active metabolite, 4-hydroxytamoxifen, in rats. Tamoxifen and baicalein interact with cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), and the increase in the use of health supplements may result in baicalein being taken concomitantly with tamoxifen as a combination therapy to treat orprevent cancer diseases. Pharmacokinetic parameters of tamoxifen and 4-hydroxytamoxifen were determined in rats after an oral administration of tamoxifen (10 mg/kg) to rats in the presence and absence of baicalein (0.5, 3, and 10 mg/kg). Compared to the oral control group (given tamoxifen alone), the area under the plasma concentration-time curve and the peak plasma concentration of tamoxifen were significantly increased by 47.6–89.1% and 54.8–100.0%, respectively. The total body clearance was significantly decreased (3 and 10 mg/kg) by baicalein. Consequently, the absolute bioavailability of tamoxifen in the presence of baicalein (3 and 10 mg/kg) was significantly increased by 47.5–89.1% compared with the oral control group (20.2%). The metabolite-parent AUC ratio of tamoxifen was significantly reduced, implying that the formation of 4-hydroxytamoxifen was considerably affected by baicalein. Baicalein enhanced the oral bioavailability of tamoxifen, which may be mainly attributable to inhibition of the CYP3A4-mediated metabolism of tamoxifen in the small intestine and/or in the liver, and inhibition of the P-gp efflux pump in the small intestine and/or reduction of total body clearance by baicalein.

Key words

Tamoxifen 4-Hydroxytamoxifen Baicalein Pharmacokinetics CYP3A4 P-gp Rats 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Bogaards, J. J., Bertrand, M., Jackson, P., Oudshoorn, M. J., Weaver, R. J., van Bladeren, P. J., and Walther, B., Determining the best animal model for human cytochrome P450 activities: a comparison of mouse, rat, rabbit, dog, micropig, monkey and man. Xenobiotica, 30, 1131–1152 (2000).PubMedCrossRefGoogle Scholar
  2. Borgna, J. L. and Rochefort, H., Hydroxylated metabolites of tamoxifen are formed in vivo and bound to estrogen receptor in target tissues. J. Biol. Chem., 256, 859–868 (1981).PubMedGoogle Scholar
  3. Buckley, M. M. and Goa, K. L., Tamoxifen. A reappraisal of its pharmacodynamic and pharmacokinetic properties, and therapeutic use. Drugs, 37, 451–490 (1989).PubMedCrossRefGoogle Scholar
  4. Cao, X., Gibbs, S. T., Fang, L., Miller, H. A., Landowski, C. P., Shin, H. C., Lennernas, H., Zhong, Y., Amidon, G. L., Yu, L. X., and Sun, D., Why is it challenging to predict intestinal drug absorption and oral bioavailability in human using rat model. Pharm. Res., 23, 1675–1686 (2006).PubMedCrossRefGoogle Scholar
  5. Chi, Y. S., Lim, H., Park, H., and Kim, H. P., Effects of wogonin, a plant flavone from Scutellaria radix, on skin inflammation: in vivo regulation of inflammation-associated gene expression. Biochem. Pharmacol., 66, 1271–1278 (2003).PubMedCrossRefGoogle Scholar
  6. Chieli, E., Romiti, N., Cervelli, F., and Tongiani, R., Effects of flavonols on P-glycoprotein activity in cultured rat hepatocytes. Life Sci., 57, 1741–1751 (1995).PubMedCrossRefGoogle Scholar
  7. Coezy, E., Borgna, J. L., and Rochefort, H., Tamoxifen and metabolites in MCF7 cells: correlation between binding to estrogen receptor and inhibition of cell growth. Cancer Res., 42, 317–323 (1982).PubMedGoogle Scholar
  8. Crespi, C. L., Miller, V. P., and Penman, B. W., Microtiter plate assays for inhibition of human, drug-metabolizing cytochromes P450. Anal. Biochem., 248, 188–190 (1997).PubMedCrossRefGoogle Scholar
  9. Crewe, H. K., Ellis, S. W., Lennard, M. S., and Tucker, G. T., Variable contribution of cytochromes P450 2D6, 2C9 and 3A4 to the 4-hydroxylation of tamoxifen by human liver microsomes. Biochem. Pharmacol., 53, 171–178 (1997).PubMedCrossRefGoogle Scholar
  10. Cummins, C. L., Jacobsen, W., and Benet, L. Z., Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4. J. Pharmacol. Exp. Ther., 300, 1036–1045 (2002).PubMedCrossRefGoogle Scholar
  11. Di Pietro, A., Conseil, G., Pérez-Victoria, J. M., Dayan, G., Baubichon-Cortay, H., Trompier, D., Steinfels, E., Jault, J. M., de Wet, H., Maitrejean, M., Comte, G., Boumendjel, A., Mariotte, A. M., Dumontet, C., McIntosh, D. B., Goffeau, A., Castanys, S., Gamarro, F., and Barron, D., Modulation by flavonoids of cell multidrug resistance mediated by Pglycoprotein and related ABC transporters. Cell. Mol. Life Sci., 59, 307–322 (2002).PubMedCrossRefGoogle Scholar
  12. Dixon, R. A. and Steele, C. L., Flavonoids and isoflavonoids -a gold mine for metabolic engineering. Trends Plant Sci., 4, 394–400 (1999).PubMedCrossRefGoogle Scholar
  13. Fried, K. M. and Wainer, I. W., Direct determination of tamoxifen and its four major metabolites in plasma using coupled column high-performance liquid chromatography. J. Chromatogr. B Biomed. Appl., 655, 261–268 (1994).PubMedCrossRefGoogle Scholar
  14. Gant, T. W., O’Connor, C. K., Corbitt, R., Thorgeirsson, U., and Thorgeirsson, S. S., In vivo induction of liver P-glycoprotein expression by xenobiotics in monkeys. Toxicol. Appl. Pharmacol., 133, 269–276 (1995).PubMedCrossRefGoogle Scholar
  15. Guengerich, F. P., Martin, M. V., Beaune, P. H., Kremers, P., Wolff, T., and Waxman, D. J., Characterization of rat and human liver microsomal cytochrome P-450 forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug metabolism. J. Biol. Chem., 261, 5051–5060 (1986).PubMedGoogle Scholar
  16. Han, C. Y., Cho, K. B., Choi, H. S., Han, H. K., and Kang, K. W., Role of FoxO1 activation in MDR1 expression in adriamycin-resistant breast cancer cells. Carcinogenesis, 29, 1837–1844 (2008).PubMedCrossRefGoogle Scholar
  17. Huang, Y., Tsang, S. Y., Yao, X., and Chen, Z. Y., Biological properties of baicalein in cardiovascular system. Curr. Drug Targets Cardiovasc. Haematol. Disord., 5, 177–184 (2005).PubMedCrossRefGoogle Scholar
  18. Jaiyesimi, I. A., Buzdar, A. U., Decker, D. A., and Hortobagyi, G. N., Use of tamoxifen for breast cancer: twenty-eight years later. J. Clin. Oncol., 13, 513–529 (1995).PubMedGoogle Scholar
  19. Johnson, M. D., Zuo, H., Lee, K. H., Trebley, J. P., Rae, J. M., Weatherman, R. V., Desta, Z., Flockhart, D. A., and Skaar, T. C., Pharmacological characterization of 4-hydroxy-Ndesmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res. Treat., 85, 151–159 (2004).PubMedCrossRefGoogle Scholar
  20. Kaminsky, L. S. and Fasco, M. J., Small intestinal cytochromes P450. Crit. Rev. Toxocol., 21, 407–422 (1991).CrossRefGoogle Scholar
  21. Kelly, P. A., Wang, H., Napoli, K. L., Kahan, B. D., and Strobel, H. W., Metabolism of cyclosporine by cytochromes P450 3A9 and 3A4. Eur. J. Drug Metab. Pharmacokinet., 24, 321–328 (1999).PubMedCrossRefGoogle Scholar
  22. Kim, C. S., Choi, S. J., Park, C. Y., Li, C., and Choi, J. S., Effects of silybinin on the pharmacokinetics of tamoxifen and its active metabolite, 4-hydroxytamoxifen in rats. Anticancer Res., 30, 79–85 (2010).PubMedGoogle Scholar
  23. Kimura, Y., Okuda, H., and Ogita, Z., Effects of flavonoids isolated from scutellariae radix on fibrinolytic system induced by trypsin in human umbilical vein endothelial cells. J. Nat. Prod., 60, 598–601 (1997).PubMedCrossRefGoogle Scholar
  24. Lee, H., Wang, H. W., Su, H. Y., and Hao, N. J., The structureactivity relationships of flavonoids as inhibitors of cytochrome P-450 enzymes in rat liver microsomes and the mutagenicity of 2-amino-3-methyl-imidazo[4,5-f]quinoline. Mutagenesis, 9, 101–106 (1994).PubMedCrossRefGoogle Scholar
  25. Lee, Y., Yeo, H., Liu, S. H., Jiang, Z., Savizky, R. M., Austin, D. J., and Cheng, Y. C., Increased anti-P-glycoprotein activity of baicalein by alkylation on the A ring. J. Med. Chem., 47, 5555–5566 (2004).PubMedCrossRefGoogle Scholar
  26. Lewis, D. F. V., Cytochrome P450. Substrate specificity and metabolism. In: Cytochromes P450. Structure, Function, and Mechanism. Taylor & Francis, Bristol, pp. 122–123, (1996).Google Scholar
  27. Li-Weber, M., New therapeutic aspects of flavones: the anticancer properties of Scutellaria and its main active constituents Wogonin, Baicalein and Baicalin. Cancer Treat. Rev., 35, 57–68 (2009).PubMedCrossRefGoogle Scholar
  28. Lin, C. C. and Shieh, D. E., The anti-inflammatory activity of Scutellaria rivularis extracts and its active components, baicalin, baicalein and wogonin. Am. J. Chin. Med., 24, 31–36 (1996).PubMedCrossRefGoogle Scholar
  29. Ma, S. C., Du, J., But, P. P., Deng, X. L., Zhang, Y. W., Ooi, V. E., Xu, H. X., Lee, S. H., and Lee, S. F., Antiviral Chinese medicinal herbs against respiratory syncytial virus. J. Ethnopharmacol., 79, 205–211 (2002).PubMedCrossRefGoogle Scholar
  30. Mani, C., Gelboin, H. V., Park, S. S., Pearce, R., Parkinson, A., and Kupfer, D., Metabolism of the antimammary cancer antiestrogenic agent tamoxifen. I. Cytochrome P-450-catalyzed N-demethylation and 4-hydroxylation. Drug Metab. Dispos., 21, 645–656 (1993).PubMedGoogle Scholar
  31. Matsuzaki, Y., Kurokawa, N., Terai, S., Matsumura, Y., Kobayashi, N., and Okita, K., Cell death induced by baicalein in human hepatocellular carcinoma cell lines. Jpn. J. Cancer Res., 87, 170–177 (1996).PubMedCrossRefGoogle Scholar
  32. Rao, U. S., Fine, R. L., and Scarborough, G. A., Antiestrogens and steroid hormones: substrates of the human Pglycoprotein. Biochem. Pharmacol., 48, 287–292 (1994).PubMedCrossRefGoogle Scholar
  33. Rhoads, C. P., Report on a cooperative study of nitrogen mustard (HN2) therapy of neoplastic disease. Trans. Assoc. Am. Physicians, 60, 110–117 (1947).PubMedGoogle Scholar
  34. Shin, S. C., Choi, J. S., and Li, X., Enhanced bioavailability of tamoxifen after oral administration of tamoxifen with quercetin in rats. Int. J. Pharm., 313, 144–149 (2006).PubMedCrossRefGoogle Scholar
  35. Shin, S. C. and Choi, J. S., Effects of epigallocatechin gallate on the oral bioavailability and pharmacokinetics of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats. Anticancer Drugs, 20, 584–588 (2009).PubMedCrossRefGoogle Scholar
  36. Stearns, V., Johnson, M. D., Rae, J. M., Morocho, A., Novielli, A., Bhargava, P., Hayes, D. F., Desta, Z., and Flockhart, D. A., Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J. Natl. Cancer Inst., 95, 1758–1764 (2003).PubMedCrossRefGoogle Scholar
  37. Sutherland, L., Ebner, T., and Burchell, B., The expression of UDP-glucuronosyltransferases of the UGT1 family in human liver and kidney and in response to drugs. Biochem. Pharmacol., 45, 295–301 (1993).PubMedCrossRefGoogle Scholar
  38. Turgeon, D., Carrier, J. S., Lévesque, E., Hum, D. W., and Bélanger, A., Relative enzymatic activity, protein stability, and tissue distribution of human steroid-metabolizing UGT2B subfamily members. Endocrinology, 142, 778–787 (2001).PubMedCrossRefGoogle Scholar
  39. Wacher, V. J., Wu, C. Y., and Benet, L. Z., Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol. Carcinog., 13, 129–134 (1995).PubMedCrossRefGoogle Scholar
  40. Wacher, V. J., Silverman, J. A., Zhang, Y., and Benet, L. Z., Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics. J. Pharm. Sci., 87, 1322–1330 (1998).PubMedCrossRefGoogle Scholar
  41. Wang, C. Z., Mehendale, S. R., and Yuan, C. S., Commonly used antioxidant botanicals: active constituents and their potential role in cardiovascular illness. Am. J. Chin. Med., 35, 543–558 (2007).PubMedCrossRefGoogle Scholar
  42. Wang, H. K., Xia, Y., Yang, Z. Y., Natschke, S. L., and Lee, K. H., Recent advances in the discovery and development of flavonoids and their analogues as antitumor and anti-HIV agents. Adv. Exp. Med. Biol., 439, 191–225 (1998).PubMedCrossRefGoogle Scholar
  43. Watkins, P. B., The barrier function of CYP3A4 and P-glycoprotein in the small bowel. Adv. Drug Deliv. Rev., 27, 161–170 (1997).PubMedCrossRefGoogle Scholar
  44. Wolozin, B., Kellman, W., Ruosseau, P., Celesia, G. G., and Siegel, G., Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch. Neurol., 57, 1439–1443 (2000).PubMedCrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea and Springer Netherlands 2011

Authors and Affiliations

  • Cheng Li
    • 1
    • 2
  • Minhee Kim
    • 1
  • HongSeok Choi
    • 1
  • JunShik Choi
    • 1
    • 3
    Email author
  1. 1.BK21 project team, College of PharmacyChosun UniversityGwangjuKorea
  2. 2.College of PharmacyYanbian UniversityJilinChina
  3. 3.College of PharmacyChosun UniversityGwangjuKorea

Personalised recommendations