Skip to main content
SpringerLink
Log in

Effects of myricetin on the bioavailability of doxorubicin for oral drug delivery in Rats: Possible role of CYP3A4 and P-glycoprotein inhibition by myricetin

  • Drug Actions
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

The purpose of this study was to investigate the effect of oral myricetin on the bioavailability and pharmacokinetics of orally and intravenously administered doxorubicin (DOX) in rats for oral delivery. The effect of myricetin on the P-glycoprotein (P-gp) and CYP3A4 activity was also evaluated. Myricetin inhibited CYP3A4 enzyme activity with 50% inhibition concentration of 7.8 μM. In addition, myricetin significantly enhanced the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-gp. The pharmacokinetic parameters of DOX were determined in rats after oral (40 mg/kg) or intravenous (10 mg/kg) administration of DOX to rats in the presence and absence of myricetin (0.4, 2 or 10 mg/kg). Compared to the control group, myricetin significantly (p < 0.05, 2 mg/kg; p < 0.01, 10 mg/kg) increased the area under the plasma concentration-time curve (AUC, 51–117% greater) of oral DOX. Myricetin also significantly (p < 0.05, 2 mg/kg; p < 0.01, 10 mg/kg) increased the peak plasma concentration of DOX. Consequently, the absolute bioavailability of DOX was increased by myricetin compared to that in the control group, and the relative bioavailability of oral DOX was increased by 1.51- to 2.17-fold. The intravenous pharmacokinetics of DOX were not affected by the concurrent use of myricetin in contrast to the oral administration of DOX. Accordingly, the enhanced oral bioavailability in the presence of myricetin, while there was no significant change in the intravenous pharmacokinetics of DOX, could be mainly due to the increased intestinal absorption via P-gp inhibition by myricetin rather than to the reduced elimination of DOX. These results suggest that the increase in the oral bioavailability of DOX might be mainly attributed to enhanced absorption in the gastrointestinal tract via the inhibition of P-gp and to reduced first-pass metabolism of DOX due to inhibition of CYP3A in the small intestine and/or in the liver by myricetin.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Alarcón de la Lastra, C., Martín, M. J., and Motilva, V., Antiulcer and gastroprotective effects of quercetin: a gross and histologic study. Pharmacology, 48, 56–62 (1994).

    Article  PubMed  Google Scholar 

  • Andersen, A., Warren, D. J., and Slordal, L., A sensitive and simple high-performance liquid chromatographic method for the determination of doxorubicin and its metabolites in plasma. Ther. Drug Monit., 15, 455–461 (1993).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Cordon-Cardo, C., O’Brien, J. P., Casals, D., Bertino, J. R., and Melamed, M. R., Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J. Histochem. Cytochem., 38, 1277–1287 (1990).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Dixon, R. A. and Steele, C. L., Flavonoids and isoflavonoids — a gold mine for metabolic engineering. Trends Plant Sci., 4, 394–400 (1999).

    Article  PubMed  Google Scholar 

  • Fakhoury, M., Litalien, C., Medard, Y., Cave, H., Ezzahir, N., Peuchmaur, M., and Jacqz-Aigrain, E., Localization and mRNA expression of CYP3A and P-glycoprotein in human duodenum as a function of age. Drug Metab. Dispos., 33, 1603–1607 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Fojo, A. T., Shen, D. W., Mickley, L. A., Pastan, I., and Gottesman, M. M., Intrinsic drug resistance in human kidney cancer is associated with expression of a human multidrug-resistance gene. J. Clin. Oncol., 5, 1922–1927 (1987).

    PubMed  CAS  Google Scholar 

  • Gibaldi, M. and Perrier, D., Pharmacokinetics (2nd edn), Marcel-Dekker, New York, (1982).

    Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • Gustafson, D. L., Merz, A. L., and Long, M. E., Pharmacokinetics of combined doxorubicin and paclitaxel in mice. Cancer Lett., 220, 161–169 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Häkkinen, S. H., Kärenlampi, S. O., Heinonen, I. M., Mykkänen, H. M., and Törrönen, A. R., Content of the flavonols quercetin, myricetin, and kaempferol in 25 edible berries. J. Agric. Food Chem., 47, 2274–2279 (1999).

    Article  PubMed  Google Scholar 

  • Ito, K., Kusuhara, H., and Sugiyama, Y., Effects of intestinal CYP3A4 and P-glycoprotein on oral drug absorption-theoretical approach. Pharm. Res., 16, 225–231 (1999).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Kitagawa, S., Nabekura, T., Takahashi, T., Nakamura, Y., Sakamoto, H., Tano, H., Hirai, M., and Tsukahara, G., Structure-activity relationships of the inhibitory effects of flavonoids on P-glycoprotein-mediated transport in KBC2 cells. Biol. Pharm. Bull., 28, 2274–2278 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Lee, H. J. and Lee, M. G., Effects of dexamethasone on the pharmacokinetics of adriamycin after intravenous administration to rats. Res. Commun. Mol. Pathol. Pharmacol., 105, 87–96 (1999).

    PubMed  CAS  Google Scholar 

  • 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 

  • Merkel, D. E., Fuqua, S. A. W., Tandom, A. K., Hill, S. M., Buzdar, A. U., and McGuire, W. L., Electrophoretic analysis of 248 clinical breast cancer specimens for P-glycoprotein overexpression of gene amplification. J. Clin. Oncol., 7, 1129–1136 (1989).

    PubMed  CAS  Google Scholar 

  • Nijveldt, R. J., van Nood, E., van Hoorn, D. E., Boelens, P. G., van Norren, K., and van Leeuwen, P. A., Flavonoids: a review of probable mechanisms of action and potential applications. Am. J. Clin. Nutr., 74, 418–425 (2001).

    PubMed  CAS  Google Scholar 

  • Ohnishi, E. and Bannai, H., Quercetin potentiates TNF-induced antiviral activity. Antiviral Res., 22, 327–331 (1993).

    Article  PubMed  CAS  Google Scholar 

  • Pichard, L., Gillet, G., Fabre, I., Dalet-Beluche, I., Bonfils, C., Thenot, J. P., and Maurel, P., Identification of the rabbit and human cytochromes P-450IIIA as the major enzymes involved in the N-demethylation of diltiazem. Drug Metab. Dispos., 18, 711–719 (1990).

    PubMed  CAS  Google Scholar 

  • Shin, S. C., Li, C., and Choi, J. S., Effects of baicalein, an antioxidant, on the bioavailability of doxorubicin in rats: possible role of P-glycoprotein inhibition by baicalein. Pharmazie, 64, 579–583 (2009).

    PubMed  CAS  Google Scholar 

  • Smylie, M. G., Wong, R., Mihalcioiu, C., Lee, C., and Pouliot, J. F., A phase II, open label, monotherapy study of liposomal doxorubicin in patients with metastatic malignant melanoma. Invest. New Drugs, 25, 155–159 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Speth, P. A. J., van Hoesel, Q. G., and Haanen, C., Clinical pharmacokinetics of doxorubicin. Clin. Pharmacokinet., 15, 15–31 (1988).

    Article  PubMed  CAS  Google Scholar 

  • Takahama, U., Inhibition of lipoxygenase-dependent lipid peroxidation by quercetin: Mechanism of antioxidative function. Phytochemistry, 24, 1443–1446 (1985).

    Article  CAS  Google Scholar 

  • Václavíková, R., Horský, S., Simek, P., and Gut, I., Paclitaxel metabolism in rat and human liver microsomes is inhibited by phenolic antioxidants. Naunyn. Schmiedebergs Arch. Pharmacol., 368, 200–209 (2003).

    Article  PubMed  Google Scholar 

  • von Moltke, L. L., Weemhoff, J. L., Bedir, E., Khan, I. A., Harmatz, J. S., Goldman, P., and Greenblatt, D. J., Inhibition of human cytochromes P450 by components of Ginkgo biloba. J. Pharm. Pharmacol., 56, 1039–1044 (2004).

    Article  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Wang, E., Lew, K., Barecki, M., Casciano, C. N., Clement, R. P., and Johnson, W. W., Quantitative distinctions of active site molecular recognition by P-glycoprotein and cytochrome P450 3A4. Chem. Res. Toxicol., 14, 1596–1603 (2001).

    Article  PubMed  CAS  Google Scholar 

  • 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., 10, 1439–1443 (2000).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. College of Medicine, Chosun University, Gwangju, 501-759, Korea

    Sang-Joon Choi

  2. College of Pharmacy, Chonnam National University, Gwangju, 500-757, Korea

    Sang-Chul Shin

  3. College of Pharmacy, Chosun University, Gwangju, 501-759, Korea

    Jun-Shik Choi

Authors
  1. Sang-Joon Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sang-Chul Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jun-Shik Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jun-Shik Choi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Choi, SJ., Shin, SC. & Choi, JS. Effects of myricetin on the bioavailability of doxorubicin for oral drug delivery in Rats: Possible role of CYP3A4 and P-glycoprotein inhibition by myricetin. Arch. Pharm. Res. 34, 309–315 (2011). https://doi.org/10.1007/s12272-011-0217-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-011-0217-x

Key words

Search

Navigation