新型抗肿瘤药物LS-177在大鼠体内的排泄研究

张伦会, 刘珍珍, 陈晓辉, 刘亿

中国药学杂志 ›› 2018, Vol. 53 ›› Issue (2) : 129-135.

PDF(1735 KB)
PDF(1735 KB)
中国药学杂志 ›› 2018, Vol. 53 ›› Issue (2) : 129-135. DOI: 10.11669/cpj.2018.02.011
论 著

新型抗肿瘤药物LS-177在大鼠体内的排泄研究

  • 张伦会1a, 刘珍珍2, 陈晓辉3, 刘亿1b*
作者信息 +

Excretion of a Novel Anticancer LS-177 in Rats

  • ZHANG Lun-hui1a, LIU Zhen-zhen2, CHEN Xiao-hui3, LIU Yi1b*
Author information +
文章历史 +

摘要

目的 研究LS-177在大鼠体内的排泄情况。方法 建立快速、灵敏的UPLC-MS/MS分析方法测定单次灌胃给予50.0 mg·kg-1的LS-177混悬液后,LS-177原型药物自雄雌大鼠尿液、胆汁和粪便中的排泄量。结果 大鼠灌胃给药后,尿液96 h内、胆汁24 h内的累积排泄百分率具有明显的雌雄差异(P<0.05),粪便96 h内的雌雄差异不明显( P>0.05)。结论 原型药物在尿液、胆汁和粪便中总的回收量约占给药剂量的50%,其中主要是由粪便排出体外,推测LS-177口服吸收差是其生物利用度低的主要原因。

Abstract

OBJECTIVE To study the excretion profile of LS-177 in rats. METHODS A selective, sensitive and accurate UPLC-MS/MS assay was developed and validated for the determination of LS-177 in rat urine, bile and feces. RESULTS After oral administration of LS-177 oral suspension at the dose of 50 mg·kg-1, there was significant difference in the excretion percentages of LS-177 between male and female rats both in urine and bile. No significant difference was observed in the excretion of LS-177 through feces.CONCLUSION The data suggests that unabsorbed LS-177 excretion in feces is the main excretion pathway, indicating that poor oral absorption is the main cause of low bioavailability.

关键词

LS-177 / 液相色谱质谱联用法 / 排泄 / 尿液 / 粪便 / 胆汁 / 肿瘤

Key words

LS-177 / UPLC-MS/MS / excretion / urine / feces / bile / cancer

引用本文

导出引用
张伦会, 刘珍珍, 陈晓辉, 刘亿. 新型抗肿瘤药物LS-177在大鼠体内的排泄研究[J]. 中国药学杂志, 2018, 53(2): 129-135 https://doi.org/10.11669/cpj.2018.02.011
ZHANG Lun-hui, LIU Zhen-zhen, CHEN Xiao-hui, LIU Yi. Excretion of a Novel Anticancer LS-177 in Rats[J]. Chinese Pharmaceutical Journal, 2018, 53(2): 129-135 https://doi.org/10.11669/cpj.2018.02.011
中图分类号: R954   

参考文献

[1] HUO L, HSU J L, HYNG M C. Receptor tyrosine kinases in the nucleus: nuclear functions and therapeutic implications in cancers[J]. Nuclear Signaling Pathways and Targeting Transcription in Cancer, 2014(21):189-229.
[2] BRANTLEY-SIEDERS D M, CHEN J. Eph receptor tyrosine kinases in angiogenesis: from development to disease[J]. Angiogenesis, 2004, 7(1): 17-28.
[3] JIMENO A, HIDALGO M. Multitargeted therapy: can promiscuity be praised in an era of political correctness?[J]. Crit Rev Oncolhematol, 2006, 59(2): 150-158.
[4] SONG Y N, ZHANG H R, YIN D D, et al. Advances in research of small molecule tyrosine kinase inhibitors for targeted cancer therapy[J]. Chin Pharm J(中国药学杂志), 2016,51(3):165-170.
[5] DI RENZO M F, OLIVERO M, KATSAROS D, et al. Overexpression of the Met/HGF receptor in ovarian cancer[J]. Int J cancer, 1994, 58(5): 658-662.
[6] WONG A S, PELECH S L, WOO M M, et al. Coexpression of hepatocyte growth factor-Met: an early step in ovarian carcinogenesis?[J]. Oncogene, 2001, 20(11): 1318-1328.
[7] QIAN C N, GUO X, CAO B, et al. Met protein expression level correlates with survival in patients with late-stage nasopharyngeal carcinoma[J]. Cancer Res, 2002, 62(2): 589-596.
[8] WAGATSUMA S, KONNO R, SATO S, et al. Tumor angiogenesis, hepatocyte growth factor, and c-Met expression in endometrial carcinoma[J]. Cancer, 1998, 82(3): 520-530.
[9] MAULIK G, SHRIKHANDE A, KIJIMA T, et al. Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition[J]. Cytokine Growth Factor Rev, 2002, 13(1): 41-59.
[10] WU C W, LI A F, CHI C W, et al. Hepatocyte growth factor and Met/HGF receptors in patients with gastric adenocarcinoma[J]. Oncol Reports, 1998, 5(4): 817-839.
[11] GAO X, DIAO L M, CHEN H L, et al. Expression of hepatocyte growth factor and its receptor in non-small cell lung carcinoma and its significance[J]. J Practical Oncol(实用肿瘤杂志), 2005, 20(1): 17-20.
[12] SCHMIDT L, DUH F M, CHEN F, et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas[J]. Nature Genetics, 1997, 16(1): 68-73.
[13] LI S, ZHAO Y, WANG K, et al. Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1, 4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors[J]. Bioorg Med Chem, 2013, 21(11): 2843-2855.
[14] TANG Q, ZHAO Y, DU X, et al. Design, synthesis, and structure-activity relationships of novel 6, 7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents[J]. Eur J Med Chem, 2013, 69(69c): 77-89.
[15] CHOUEIRI T K, VAISHAMPAYAN U, ROSENBERG J E, et al. Phase Ⅱ and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma[J]. J Clin Oncol, 2013, 31(2): 181-186.
[16] DING W,ZHAO Y L, WANG X R,et al. Determination of eight kinds of residual solvents in LS-177 by headspace gas chromatography[J]. J Shenyang Pharm Univ(沈阳药科大学学报), 2014, 31(8): 618-621.
[17] JU P, LIU Z Z, JIANG Y, et al. Determination of a novel anticancer c-Met inhibitor LS-177 in rat plasma and tissues with a validated UPLC-MS/MS method: application to pharmacokinetics and tissue distribution study[J]. Bioem Chromatog, 2015,29(7):1103-1111.
[18] ZHANG L H,JU P, ZHOU F F,et al. The absolute bioavailability investigation of LS-177 in rats using ultra-performance liquid chromatography tandem mass spectrometry[J]. Drug Testing Anal,2015,7(9): 756-762.
[19] FDA Guidance for Industry: Bioanalytical Method Validation[S]. Rockville, MD: US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research,2001.
PDF(1735 KB)

Accesses

Citation

Detail

段落导航
相关文章

/