Abstract
Quercetin, a flavonoid, is an inhibitor of P-glycoprotein-mediated efflux transport, and its oxidative metabolism is catalyzed by CYP enzymes. Thus, it is expected that the pharmacokinetics of both intravenous and oral doxorubicin can be changed by quercetin. The purpose of this study was to investigate the effect of oral quercetin on the bioavailability and pharmacokinetics of orally and intravenously administered doxorubicin in rats. The effects of quercetin on the P-glycoprotein (P-gp) and CYP3A4 activities were also evaluated. Quercetin inhibited CYP3A4 enzyme activity in a concentration-dependent manner with a 50% inhibition concentration (IC50) of 1.97 μM. In addition, quercetin significantly enhanced the intracellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. The pharmacokinetic parameters of doxorubicin were determined in rats after oral (50 mg/kg) or intravenous (10 mg/kg) administration of doxorubicin to rats in the presence and absence of quercetin (0.6, 3 or 15 mg/kg). Compared to control, quercetin significantly (p < 0.05 for 0.6 mg/kg, p < 0.01 for 3 and 15 mg/kg) increased the area under the plasma concentration-time curve (AUC0−∞, 31.2-136.0% greater) of oral doxorubicin. Quercetin also significantly increased the peak plasma concentration (Cmax) of doxorubicin, while there was no significant change in Tmax and T1/2 of doxorubicin. Consequently, the absolute bioavailability of doxorubicin was increased by quercetin compared to control, and the relative bioavailability of oral doxorubicin was increased by 1.32 to 2.36 fold. In contrast, the pharmacokinetics of intravenous doxorubicin were not affected by quercetin. These results suggest that the quercetin-induced increase in bioavailability of oral doxorubicin can be attributed to enhanced doxorubicin absorption in the gastrointestinal tract via quercetin-induced inhibition of P-gp and reduced first-pass metabolism of doxorubicin due to quercetin-induced inhibition of CYP3A in the small intestine and/or in the liver rather than reduced renal and/or hepatic elimination of doxorubicin. Therefore, it appears that the development of oral doxorubicin preparations is possible, which will be more convenient than the intravenous dosage forms. Therefore, concurrent use of quercetin provides a therapeutic benefit — it increases the bioavailability of doxorubicin administered orally.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Andersen, A., Warren, D. J., and Slørdal, 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).
Avendaño, C. and Menéndez, J. C., Inhibitors of multidrug resistance to antitumor agents (MDR). Curr. Med. Chem., 9, 159–193 (2002).
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).
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).
Choi, J. S., Jo, B. W., and Kim, Y. C., Enhanced paclitaxel bioavailability after oral administration of paclitaxel or prodrug to rats pretreated with quercetin. Eur. J. Pharm. Biopharm., 57, 313–318 (2004).
Cooray, H. C., Janvilisri, T., van Veen, H. W., Hladky, S. B., and Barrand, M. A., Interaction of the breast cancer resistance protein with plant polyphenols. Biochem. Biophys Res. Commun., 317, 269–275 (2004).
Cordon-Cardo, C., O’Brien, J. P., Boccia, J., 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).
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).
Dupuy, J., Larrieu, G., Sutra, J. F., Lespine, A., and Alvinerie, M., Enhancement of moxidectin bioavailability in lamb by a natural flavonoid: quercetin. Vet. Parasitol., 112, 337–347 (2003).
Fakhoury, M., Litalien, C., Medard, Y., Cavé, 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).
Ferry, D. R., Smith, A., Malkhandi, J., Fyfe, D. W., deTakats, P. G., Anderson, D., Baker, J., and Kerr, D. J., Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin. Cancer Res., 2, 659–668 (1996).
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).
Gottesman, M. M., Fojo, T., and Bates, S. E., Multidrug resistance in cancer: role of ATP-dependent transporters. Nat. Rev. Cancer, 2, 48–58 (2002).
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).
Gustafson, D. L., Merz, A. L., and Long, M. E., Pharmacokinetics of combined doxorubicin and paclitaxel in mice. Cancer Lett., 220, 161–169 (2005).
Hertog, M. G. L., Hollman, P. C. H., and Venema, D. P., Optimization of a quantitative HPLC determination of potentially anticarcinogenic flavonoids in vegetables and fruits. J. Agric. Food Chem., 40, 1591–1598 (1992).
Hertog, M. G., Kromhout, D., Aravanis, C., Blackburn, H., Buzina, R., Fidanza, F., Giampaoli, S., Jansen, A., Menotti, A., and Nedeljkovic, S., Flavonoid intake and long-term risk of coronary heart disease and cancer in the seven countries study. Arch. Intern. Med., 155, 381–386 (1995).
Kaminsky, L. S. and Fasco, M. J., Small intestinal cytochromes P450. Crit. Rev. Toxicol., 21, 407–422 (1991).
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).
Lamson, D. W. and Brignall, M. S., Antioxidants and cancer. III. Quercetin. Altern. Med. Rev., 5, 196–208 (2000).
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).
Li, X. and Choi, J. S., Effects of quercetin on the pharmacokinetics of Etoposide after oral or intravenous administration of etoposide in rats. Anticancer Res., 29, 1411–1415 (2009).
Merkel, D. E., Fuqua, S. A., 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).
Miniscalco, A., Lundahl, J., Regårdh, C. G., Edgar, B., and Eriksson, U. G., Inhibition of dihydropyridine metabolism in rat and human liver microsomes by flavonoids found in grapefruit juice. J. Pharmacol. Exp. Ther., 261, 1195–1199 (1992).
Scambia, G., Ranelletti, F. O., Panici, P. B., De Vincenzo, R., Bonanno, G., Ferrandina, G., Piantelli, M., Bussa, S., Rumi, C., and Cianfriglia, M., Quercetin potentiates the effect of adriamycin in a multidrug-resistant MCF-7 human breastcancer cell line: P-glycoprotein as a possible target. Cancer Chemother. Pharmacol., 34, 459–464 (1994).
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).
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).
Speth, P. A., van Hoesel, Q. G., and Haanen, C., Clinical pharmacokinetics of doxorubicin. Clin. Pharmacokinet., 15, 15–31 (1988).
van Zanden, J. J., Wortelboer, H. M., Bijlsma, S., Punt, A., Usta, M., Bladeren, P. J., Rietjens, I. M., and Cnubben, N. H., Quantitative structure activity relationship studies on the flavonoid mediated inhibition of multidrug resistance proteins 1 and 2. Biochem. Pharmacol., 69, 699–708 (2005).
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).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Choi, JS., Piao, YJ. & Kang, K.W. Effects of quercetin on the bioavailability of doxorubicin in rats: Role of CYP3A4 and P-gp inhibition by quercetin. Arch. Pharm. Res. 34, 607–613 (2011). https://doi.org/10.1007/s12272-011-0411-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-011-0411-x