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Effects of Morin on the Bioavailability of Doxorubicin for Oral Delivery in Rats

  • Published : 2009.08.20

Abstract

The purpose of this study was to investigate the effects of morin, an antioxidant, on the bioavailability of doxorubicin (DOX) in rats. Thus, DOX was administered intravenously (10 mg/kg) or orally (50 mg/kg) with or without oral morin (0.5, 3 and 10 mg/kg). In the presence of morin, the total area under the plasma concentration-time curve (AUC) of DOX was significantly greater than that of the control. In the presence of 3 and 10 mg/kg of morin, the peak concentration $C_{MAX}$) was significantly higher than that of the control. Consequently, the absolute bioavailability (AB) of DOX in the presence of morin was 3.7-8.3%, which was significantly enhanced compared with those of the control group (2.7%). The relative bioavailability (RB) of DOX was 1.36 to 3.02 times higher than those of the control group. Compared to the intravenous control, the presence of morin increased the AUC of DOX, but was not significantly affected. The enhanced bioavailability of oral DOX by oral morin may be due to the inhibition of both P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A in the intestine and/or liver by morin. This result may suggest that the development of oral DOX combination with morin is feasible, which is more convenient than the i.v. dosage forms. The present study raised the awareness about the potential drug interactions by concomitant use of DOX with morin.

Keywords

References

  1. C. Avendano and J. C.Menendez, Inhibitors of multidrug resistance to antitumor agents (MDR), Curr. Med. Chem., 9, 159-193 (2002). https://doi.org/10.2174/0929867023371175
  2. M.M. Gottesman, T. Fojo and S.E. Bates, Multidrug resistance in cancer: role of ATP-dependent transporters, Nat. Rev. Cancer., 2, 48-58 (2002) https://doi.org/10.1038/nrc706
  3. C. Cordon-Cardo, J.P. O'Brien, D. Casals, J.R. Bertino and M.R. Melamed, Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues, J. Histochem. Cytochem., 38, 1277-1287 (1990) https://doi.org/10.1177/38.9.1974900
  4. A.T. Fojo, D.W. Shen, L.A. Mickley, I. Pastan and M.M. Gottesman, Intrinsic drug resistance in human kidney cancer is associated with expression of a human multidrug-resistance gene, J. Clin. Oncol., 5, 1922-1927 (1987). https://doi.org/10.1200/JCO.1987.5.12.1922
  5. D.E. Merkel, S.A.W. Fuqua, A.K. Tandom, S.M. Hill, A.U. Buzdar and W.L. McGuire, Electrophoretic analysis of 248 clinical breast cancer specimens for P-glycoprotein overexpression of gene amplification, J. Clin. Oncol., 7, 1129-1136 (1989). https://doi.org/10.1200/JCO.1989.7.8.1129
  6. E. Wang, K. Lew, M. Barecki, C.N. Casciano, R.P. Clement and W.W. Johnson, Quantitative distinctions of active site molecular recognition by P-glycoprotein and cytochrome P450 3A4, Chem. Res. Toxicol., 14, 1596-1603 (2001) https://doi.org/10.1021/tx010125x
  7. M. Fakhoury, C. Litalien, Y. Medard, H. Cave, N. Ezzahir, M. Peuchmaur and E. Jacqz-Aigrain, Localization and mRNA expression of CYP3A and P-glycoprotein in human duodenum as a function of age, Drug Metab. Dispos., 33, 1603-1607 (2005). https://doi.org/10.1124/dmd.105.005611
  8. M.H. Schwarzbach, S. Eisold, T. Burguete, F. Willeke, P. Klein-Bauernschmitt, J.R. Schlehofer, C. Herfarth, R. Ridder and von M. Knebel Doeberitz, Sensitization of sarcoma cells to doxorubicin treatment by concomitant wildtype adeno-associated virus type 2 (AAV-2) infection, Int. J. Oncol., 20, 1211-1218 (2002).
  9. F. Langer, H.O. Wintzer, M. Werner, C. Weber, T.H. Brummendorf and C.A Bokemeyer, Case of pulmonary carcinosarcoma (squamous cell carcinoma and osteosarcoma) treated with cisplatin and doxorubicin, Anticancer Res., 26, 3893-3897 (2006).
  10. P.A. Lind, G. Naucler, A. Holm, M. Gubanski and C. Svensson, Efficacy of pegylated liposomal doxorubicin in patients with advanced hepatocellular carcinoma, Acta. Oncol., 46, 230-233 (2007). https://doi.org/10.1080/02841860600693473
  11. B.B. Lundberg, G. Griffiths and H.J. Hansen, Cellular association and cytotoxicity of doxorubicin-loaded immunoliposomes targeted via Fab' fragments of an anti-CD74 antibody, Drug Deliv., 14, 171-175 (2007). https://doi.org/10.1080/10717540601036831
  12. M.G. Smylie, R. Wong, C. Mihalcioiu, C. Lee and J.F. Pouliot, A phase II, open label, monotherapy study of liposomal doxorubicin in patients with metastatic malignant melanoma, Invest. New Drugs., 25, 155-159 (2007). https://doi.org/10.1007/s10637-006-9002-y
  13. D.L. Gustafson, A.L. Merz and M.E. Long, Pharmacokinetics of combined doxorubicin and paclitaxel in mice, Cancer Lett., 220,161-169 (2005). https://doi.org/10.1016/j.canlet.2004.09.007
  14. K.T. Kivisto, H.K. Kroemer and M. Eichelbaum, The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions, Br. J. Clin. Pharmacol., 40, 523-v530 (1995). https://doi.org/10.1111/j.1365-2125.1995.tb05796.x
  15. E. Jr. Middleton, C. Kandaswami and T. Theoharides, The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer, Pharmacol. Rev., 52, 673-751 (2000).
  16. H. Lee, H.W. Wang, H.Y. Su and N.J. Hao, The structure-activity 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). https://doi.org/10.1093/mutage/9.2.101
  17. E. Chieli, N. Romiti, F. Cervelli and R. Tongiani, Effects of flavonols on P-glycoprotein activity in cultured rat hepatocytes, Life Sci., 57, 1741-1751 (1995). https://doi.org/10.1016/0024-3205(95)02152-9
  18. A. Di Pietro, G. Conseil, J. M. Perez-Victoria, G. Dayan, H. Baubichon-Cortay, D. Trompier, E. Steinfels, J. M. Jault, H. de Wet, M. Maitrejean, G. Comte, A. Boumendjel, A.M. Mariotte, C. Dumontet, D.B. McIntosh, A. Goffeau, S. Castanys, F. Gamarro and D. Barron, Modulation by flavonoids of cell multidrug resistance mediated by P-glycoprotein and related ABC transporters, Cell. Mol. Life Sci., 59, 307-322 (2002). https://doi.org/10.1007/s00018-002-8424-8
  19. L.D. Kok, Y.P. Wong, T.W. Wu, H.C. Chan, T.T. Kwok and K.P. Fung, Morin hydrate: a potential antioxidant in minimizing the free-radicals-mediated damage to cardiovascular cells by anti-tumor drugs, Life Sci., 67, 91-99 (2000). https://doi.org/10.1016/S0024-3205(00)00605-6
  20. A.R. Francis, T.K. Shetty and R.K. Bhattacharya, Modulating effect of plant flavonoids on the mutagenicity of N-methyl-N'-nitro-N-nitrosoguanidine, Carcinogenesis. 10, 1953-1955 (1989). https://doi.org/10.1093/carcin/10.10.1953
  21. S.H. Fang, Y.C. Hou, W.C. Chang, S.L. Hsiu, P.D. Chao and B.L. Chiang, Morin sulfates/glucuronides exert anti-inflammatory activity on activated macrophages and decreased the incidence of septic shock, Life Sci., 74, 743-756 (2003). https://doi.org/10.1016/j.lfs.2003.07.017
  22. S.L. Hsiu, C.W. Tsao, Y.C. Tsai, H.J. Ho and P.D. Chao, Determinations of morin, quercetin and their conjugate metabolites in serum, Biol. Pharm. Bull., 24, 967-969 (2001). https://doi.org/10.1248/bpb.24.967
  23. Y.C. Hou, P.D. Chao, H.J. Ho, C.C. Wen and S.L. Hsiu, Profound difference in pharmacokinetics between morin and its isomer quercetin in rats, J. Pharm. Pharmacol. 55, 199-203 (2003). https://doi.org/10.1211/002235702487
  24. S. Zhang and M.E. Morris, Effects of the flavonoids biochanin A, morin, phloretin, and silymarin on P-glycoprotein-mediated transport, J. Pharmacol. Exp. Ther., 304, 1258-1267 (2003). https://doi.org/10.1124/jpet.102.044412
  25. M.K. Buening, R.L. Chang, M.T. Huang, J.G. Fortner, A.W. Wood and A.H. Conney, Activation and inhibition of benzo (a) pyrene and aflatoxin B1 metabolism in human liver microsomes by naturally occurring flavonoids, Cancer Res., 41, 67-72 (1981).
  26. B.C. Choi, J.S. Choi and H.K. Han, Altered pharmacokinetics of paclitaxel by the concomitant use of morin in rats, Int. J. Pharm., 323, 81-85 (2006). https://doi.org/10.1016/j.ijpharm.2006.05.046
  27. X. Li, J.K. Yun and J.S. Choi, Effects of morin on the pharmacokinetics of etoposide in rats.. Biopharm, Drug Dispos., 28, 151-156 (2007). https://doi.org/10.1002/bdd.539
  28. S.C. Shin, Y.J. Piao and J.S. Choi, Effects of morin on the bioavailability of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats, In Vivo., 22, 391-395 (2008).
  29. A. Andersen, D.J. Warren and L. Slordal, 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). https://doi.org/10.1097/00007691-199310000-00016
  30. C.L. Cummins, W. Jacobsen and L.Z. Benet, Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4, J. Pharmacol. Exp. Ther., 300, 1036-1045 (2002). https://doi.org/10.1124/jpet.300.3.1036
  31. L.Z. Benet, C.L. Cummins and C.Y. Wu, Transporter-enzyme interactions: implications for predicting drug-drug interactions from in vitro data, Curr. Drug Metab., 4, 393-398 (2003). https://doi.org/10.2174/1389200033489389
  32. J.W. Critchfield, C.J. Welsh, J.M. Phang and G.C. Yeh, Modulation of adriamycin accumulation and efflux by flavonoids in HCT-15 colon cells. Activation of P-glycoprotein as a putative mechanism, Biochem. Pharmacol., 48, 1437-1445 (1994). https://doi.org/10.1016/0006-2952(94)90568-1
  33. G. Scambia, F.O. Ranellett, P.B. Panici, D.R. Vincenzo, G. Bonanno, G. Frrandina, M. Piantelli, S. Bussa, C. Rumi and M. Ciantriglia, Quercetin potentiates the effect of adriamycin in a multidrug-resistant MCF-7 human breast-cancer cell line: Pglycoprotein as a possible target, Cancer Chemother. Pharmacol., 36, 448-450 (1994). https://doi.org/10.1007/BF00686195
  34. V.A. Eagling, L. Profit and D.J. Back, Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-1 protease inhibitor saquinavir by grapefruit juice components, Br. J. Clin. Pharmacol., 48, 543-552 (1999). https://doi.org/10.1046/j.1365-2125.1999.00052.x