Effects of co-administraton of neferine and doxorubicin on the pharmacokinetics of doxorubicin

doi:10.5246/jcps.2015.04.029

Abstract

Abstract:

Doxorubicin is one of the anthracycline anti-neoplastic drugs widely used to treat leukemia, liver, breast, and ovarian cancers and other solid tumors. However, its clinical applications have been limited by its serious cardio-cytotoxic effects. The aim of this study was to investigate the effect of neferine, a bisbenzylisoquinoline alkaloid extracted from the green embryo in the mature lotus seed, on the pharmacokinetics of doxorubicin. The levels of doxorubicin in plasma and tissues were measured using the high performance liquid chromatography (HPLC) method. The chromatographic separation was completed on a reversed-phase C₁₈ column using acetonitrile–phosphate buffer (30:70, v/v) as the mobile phase at a flow rate of 1 mL/min and ultraviolet detectionwave length was set at 233 nm. The pharmacokinetic study found that the co-administration of neferine and doxorubicin significantly affected the pharmacokinetics of doxorubicin. There were evident changes in area under the curve (AUC), clearance (CL) and t_1/2β in group of pretreatment neferine as compared with those in group treated with doxorubicin alone. Tissue distribution analysis showed that the concentrations of doxorubicin distributed to heart, liver and kidney were statistically significant higher in group of pretreatment with neferine plus doxorubicin than those in the doxorubicin alone-group at 0.5 h and 2 h after drug administration, respectively.While the doxorubicin concentrations in spleen and lung drug were slightly increased in the group of pretreatment with neferine plus doxorubicin as compared to that of group of doxorubicin alone, the difference between two groups were not statistically significant. Therefore, the dose of doxorubicin needs to be taken into consideration when it is administrated in combination with neferine.

Key words: Neferine, Doxorubicin, Pharmacokinetics, HPLC method, Anthracycline anti-neoplastic drugs

CLC Number:

R969.1

Supporting:

Qingdan Xue, Aixia Ju, Yuhong Kang, Chunyu Zheng, Qiuhong Li. Effects of co-administraton of neferine and doxorubicin on the pharmacokinetics of doxorubicin[J]. Journal of Chinese Pharmaceutical Sciences, 2015, 24(4): 225-230.

References

[1] Tokarska, S.M.; Wallimann, T. U. C. R .Biol. 2006, 329, 657.

[2] Lefrak, E.A.; Piťha, J.; Rosenheim, S.; Gottlieb, J.A. Cancer. 1973, 32, 302-314.

[3] Liu, M.W.; Qiao, P.J.; Guo, X.M. Henan Med. Info. 1998, 6, 42-43.

[4] Qiu, Y.R.; Wang, W. Foreign Med. Sci. , 20, 214-2151999.

[5] He, X.H.; He, B.W.; Tang, B.J. J. Chinese Med. Abstr. Oncol. 2010, 2, 60-62.

[6] Najah, H.; Nasser, G.Y.; Fadhil, G.A.; Nadhem, K.H.; Bassim, I.M.; Sadiq, J.A. BMC Cardiovasc. Disord. 2012, 12, 1-7.

[7] Conklin, K.A. Integr. Cancer Ther. 2005, 4, 110-130.

[8] Li, L.H.; Takemura, G.Z.; Li, Y.W.; Miyata, S.; Esaki, M.; Okada, H.; Kanamori, H.; Khai, N.C.; Maruyama, R.; Ogino, A.; Minatoguchi, S.; Fujiwara, T.; Fujiwara, H. Circulation. 2006, 113, 535-543.

[9] Bian, J.S.; Ding, J.H.; Wang, Y.L. CJPT. 1995, 9, 280-282.

[10] Ye, Z.G.; Wang, J.H.; Sun, A.X.; Liang, A.H.; Xue, B.Y.; Li, C.Y.; Wang, L. Acta Pharm. Sin. 2001, 36, 96-99.

[11] Huang, C.H.; Li, Y.P.; Cao, P.G.; Xie, Z.X.; Qin, Z.Q. J. Huazhong Univ. Sci. Technol. 2011, 31, 488-496.

[12] Jung, H.A.; Jin, S.E.; Choi, R.J.; Kim, D.H.; Kim, Y.S.; Ryu, J.H.; Kim, D.W; Son, Y.K.; Park, J.J.; Choi, J.S. Life Sci. 2010, 87,420-430.

[13] Guo, Z.B.; Li, Q.; Cao, H.Y.; Xu, Z. J. Chin. Pharm. Sci. 2002, 11, 35-42.

[14] Yu, J.; Hu, W.S. Acta Pharm. Sin. 1997, 32, 1-4.

[15] Dong, L.; Tang, X.Q.; Cao, J.G.; Wang, Z. Chin. Pharm. Bull. 2002, 18, 43-45.

[16] Gao, Z.P.; Cao, J.G.; Huang, H.L.; Zhou, J.M. J. Hengyang Med. Coll. 1997, 25, 320-323.

[17] Bao, J.; Ling, Y.; Xi, Y.J.; Jiang, P.F.; Wen, G.M.; Cao, J.G. Chin. J. Exp. Sur. 2006, 23, 611-622.

[18] Fang, L.; Lin, N.M. J. Oncol. 2007, 13, 424-428.

[19] Scripture, C.D.; Sparreboom, A.; Figg, W.D. Lancet Oncol. 2005, 6, 780-789.

[20] Huang, Y.; Zhao, L.B.; Li, S.; Liu, Y.; Hu, B.R.; Wang, J.L.; Xiang, J.Z. Acta Pharm. Sin. 2007, 42, 1034-1040.

[21] Huang, Y.; Bai, Y.; Zhao, L.B.; Hu, T.; Hu, B.R.; Wang, J.L.; Xiang, J.Z. Biopharm. Drug Dispos. 2007, 28, 361-372.

[22] Szakacs, G.; Paterson, J.K.; Ludwig, J.A.; Genthe, C.B.; Gottesman, M.M. Nat. Rev. Drug Discov. 2006, 5, 219-234.

[23] Abbott, B.L. Hematol Oncol. 2003, 21, 115-130.

[24] Ozben, T. FEBS Lett. 2006, 53, 2903-2909.

[25] Jennifer, L. The Merck Manual. 2014. This article can be found online at http://www.merckmanuals.com/professional/ clinical-pharmacology/pharmacokinetics/drug distribution-to-issues.html.

[26] Benjamin, R.A.; Riggs, C.E.; Bachur, N.R. Cancer Res. 1977, 37, 1416-1420.

[27] Bachur, N.R.; Gordon, S.L.; Gee, M.V. Proc. Natl. Acad. Sci. USA. 1979, 76, 954-957.