Study on essential metabolites of Epothilone D in human urine by liquid

Abstract

Abstract: AIM: To investigate the essential metabolites of Epothilone D in human urine. METHODS: The urine samples of six volunteers after intervenous drop infusion of 125mg m2 were collected within 0-72 h, the samples were purified and separated through C18 solid-phase extraction column and analyzed with liquid chromatography-mass spectrometry.The potential metabolites were analyzed through comparing the TIC and SIM chromatograms of the blank urine and sample urine, and the structure of the metabolites were identified through the correlation of the full scan MSn spectra of Epothilone D and the metabolites. RESULTS: Eleven metabolites were found in human urine.There were three kinds of structure of metabolites, the metabolic ways of oxidation, hydrogenise, hydrolization and association reaction. CONCLUSION: The method was proved sensitively and selectively, and it is possible to supply a reliable reference for further study on the metabolites of Epothilones.

Key words: liquid chromatography-mass spectrometry, Epothilone D, solid-phase extraction, metabolite

CLC Number:

R969.1

ZHANG Chun-ling, ZHU Xiao-xia, QI Wen-yuan, LIU Jiang-lin, MENG Zhi-yun, WANG Yan-lin, WU Zhuo-na, SUN Guo-xiang, DOU Gui-fang. Study on essential metabolites of Epothilone D in human urine by liquid[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2009, 14(3): 307-312.

References

[1] Julien B, Shah S, Ziermann R, et al.Isolation and characterization of the epothilone biosynthetic gene cluster from Sorangium cellulosum[J].Gene, 2000, 249(1 2):153-160.
[2] Bollag DM, McQueney PA, Zhu J, et al.Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action[J].Cancer Res, 1995, 55(11): 2325-2333.
[3] Holfle GH, Bedorf N, Steinemtz H, et al.Epothilone A and B-novel 16-membered macrolides with cytotoxic activi-ty:isolation crystal structure, and confoumation in Solution[J].Angew Chem Int Ed Engl, 1996, 35(13):1567-1569.
[4] 顾勤兰, 王进欣.抗肿瘤药物埃坡霉素生物合成进展[J].中国新药杂志, 2005, 14(10):1148-1150.
[5] 顾勤兰, 尤启冬, 王进欣.抗肿瘤药物埃坡霉素的研究进展[J].江苏药学与临床研究, 2004, 10(12):20-21.
[6] 王进欣, 顾勤兰, 尤启冬, 等.新型抗肿瘤药物埃坡霉素的研究[J].药学进展, 2004, 28(8):354-361.
[7] Lee KW, Briggs JM.Comparative molecular field analysis (coMFA) study of epothilones-tubulin depolymerization inhibitiors: pharmacophore development using 3D QSAR methods[J].J Comput Aided Mol Des, 2001, 15(1):41-55.
[8] Kowalski RJ, Giannakakakou P, Hamel E.Activities of the microtubulestabilizing agents epothilone A and B with purified tubulin and in cells resistant to paclitaxel(Taxol) [J].J Bio Chem, 1997, 272(4):2534-2541.
[9] Nicolaou KC, Roschangar F, Vourloumis D.Chemical biology of epothilones [J].Angew Chem Int Ed, 1998, 37(15):2014-2045.
[10] Stachel SJ, Lee CB, Spassova M, et al.On the interactivity of complex aynthesis and tumor pharmacology in the drug discovery process:total synthesis and comparative in vivo evaluations of the 15-Aza Epothilones[J].J Org Chem, 2001, 66(12):4369-4378.
[11] Humphrey MJ, Smith DA.Role of metabolism and pharmacokinetic studies in the discovery of new drugs-Present and future perspectives[J].Xenobiotica, 1992, 22(7): 743-755.
[12] GumbletonM, Sneader W.Pharmacokinetic considerations in rational drug design[J].Clin Pharmacokinet, 1994, 26(3):161-168.
[13] 潘颖瑜, 俞英, 赖谷仙, 等.高效液相色谱-电喷雾质谱法研究人尿中a-生育酚的主要代谢产物[J].药学学报, 2008, 43(6):634-639.
[14] Li JS.Progress in the vitamin E absorption and metabolism rescarch[J].Chin J Mod Appl Pharm Sin, 2006, 10(41): 1004-1009.
[15] Sindona G.High-throughput screening of tocopherols in natural extracts[J].J Mass Spectrum, 2000, 35(11): 1360-1361.
[16] 高凯, 余伟, 杨静, 等.大鼠肝微粒体CYP3A1 2 和CYP2C9 10 参与甘草次酸羟化代谢[J].中国临床药理学与治疗学, 2007, 12(11):1255-1260.