作者：宁欣¹, 陈芙蓉¹, 张玉霞¹, 冯亚男¹, 王梦丽¹, 谢红英¹, 雍智全², 徐小平¹

作者单位：1. 四川大学华西药学院, 四川 成都 610041;
2. 广东达信生物科技有限公司, 广东 东莞 523808

关键词：XY-02;CA4P;静脉给药;HPLC;组织分布

摘要：

建立HPLC对肿瘤血管抑制剂XY-02与CA4P在大鼠体内组织分布规律的研究方法,揭示两种药物靶组织的差异与潜在的治疗特征和安全性。SD大鼠分别静脉注射XY-02(80 mg/kg)或CA4P(1 mg/kg),于给药后15,40,90 min采集大鼠心、肝、脾、肺、肾、胃、小肠、脑、子宫、睾丸等组织进行含量测定,以C18(250 mm4.6 mm5 m)为色谱柱,0.01%乙酸-甲醇(50:50,v/v)为流动相,流量为1.0 mL/min,检测波长为325 nm。XY-02和CA4P分别在0.15～750 g/mL和0.03～60 g/mL范围内线性关系良好(r0.999 5),检测限分别为17 ng/mL和 4.93 ng/mL。两种肿瘤血管抑制剂均在大鼠组织中有广泛分布和快速消除的特点,预示二者可对各种组织肿瘤具有潜在的治疗作用且体内产生蓄积的可能性小。特别是XY-02在肾脏和肝脏中分布较多,提示XY-02可对临床上较难治疗的肾癌和肝癌有更好的治疗价值;XY-02在心脏和肠道的分布较CA4P低,表明XY-02的心脏毒性和肠道的不良反应比CA4P更小,安全性更好。

Comparisons of tissue distribution of tumor vascular inhibitors XY-02 and CA4P

NING Xin¹, CHEN Furong¹, ZHANG Yuxia¹, FENG Ya'nan¹, WANG Mengli¹, XIE Hongying¹, YONG Zhiquan², XU Xiaoping¹

1. West China School of Pharmacy, Sichuan University, Chengdu 610041, China;
2. Dongguan Daxin Biotech Co., Ltd., Dongguan 523808, China

Abstract: A HPLC method was developed for the comparative study of the tissue distribution of CA4P and XY-02 in rats. The test revealed the differences in target tissues as well as the potential treatment and safety features of the two tumor vascular targeting inhibitors. After intravenous administration of XY-02 (80 mg/kg) or CA4P (1 mg/kg), samples like heart, liver, spleen, lung, stomach, intestine, brain, testis, uterus were taken at 15, 40, and 90 min after dosing. The separation was performed on a ODS column (250 mm×4.6 mm×5 μm) with mobile phase methanol-0.01% acetic acid (50:50, v/v). The wavelength was set at 325 nm and the flow rate was 1 ml/min. Calibration standards show that the excellent linearity range is 0.15-750 μg/mL for XY-02 and 0.03-60.0 μg/mL for CA4P (r>0.999 5). The lowest detectable concentration of XY-02 and CA4P is 17 ng/mL and 4.93 ng/mL, respectively. The results indicate that both XY-02 and CA4P are widely distributed and rapidly eliminated in tissues, suggesting that they may have potential treatment effect in vivo tumors in different tissues and the possibility of accumulation in vivo is little. The relatively high distribution of XY-02 in kidney and liver demonstrates that it may have a better value in treating kidney and liver cancers. Compared with CA4P, XY-02 is lower in cardiotoxicity and gastrointestinal adverse reaction and much safer.

Keywords: XY-02;CA4P;intravenous administration;HPLC;tissue distribution

2015, 41(10): 53-57  收稿日期: 2015-04-15;收到修改稿日期: 2015-05-28

基金项目: 2014年东莞市引进创新创业领军人(201476815)

作者简介: 宁欣(1991-),女,四川绵阳市人,硕士研究生,专业方向为药品质量控制和药物代谢分析。

参考文献

[1] West C M, Price P. Combretastatin A4 phosphate[J]. Anti Cancer Drugs,2004(15):179-187.
[2] Siemann D W, Chaplin D J, Walicke P A. A review and update of the current status of the vasculature-disabling agent combretastatin-A4 phosphate(CA4P)[J]. Expert Opin Investig Drugs,2009,18(2):189-197.
[3] Pettit G R, Singh S B, Hamel E, et al. Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A4[J]. Experientia,1989(45):205-211.
[4] Tozer G M, Kanthou C, Baguley B C. Disrupting tumour blood vessels[J]. Nat Rev Cancer,2005(5):423-435.
[5] Parkins C S, Holder A J, Hill S A, et al. Determinants of anti-vascular action by combretastatin A-4 phosphate: role of nitric oxide[J]. Br J Cancer,2008(3):811-816.
[6] Brooks A C, Kanthou C, Cook I H, et al. The vascular targeting agent combretastatin A-4-phosphate induces neutrophil recruitment to endothelial cells in vitro[J]. Anticancer Res,2003,23(4):3199-3206.
[7] Rustin G J, Galbraith S M, Anderson H, et al. Phase I clinical trial of weekly combretastatin A4 phosphate: clinical and pharmacokinetic results[J]. J Clin Oncol,2003(21):2815-2822.
[8] Mooney C J, Nagaiah G, Fu P, et al. A Phase II trial of fosbretabulin in advanced anaplastic thyroid carcinoma and correlation of baseline serum-soluble intracellular adhesion molecule-1 with outcome[J]. Thyroid,2009(19):233-240.
[9] Rustin G J, Shreeves G, Nathan P D, et al. A Phase Ib trial of CA4P (combretastatin A-4 phosphate), carboplatin, and paclitaxel in patients with advanced cancer[J]. Br J Cancer,2010(102):1355-1360.
[10] Zweifel M, Jayson G C, Reed N S, et al. Phase II trial of combretastatin -A 4-phos phate, carboplatin, and paclitaxel in patients with platinum-resistant ovarian cancer[J]. Ann Oncol,2011,22(9):2036-2041.
[11] 何雯雯,刘静,张洁,等. 抗癌药XY-02在大鼠体内的药物动力学[J]. 华西药学杂志,2008,23(5):577-579.
[12] Wang X, Chen Z, Che J, et al. Development of a rapid and sensitive LC-MS/MS assay for the determination of combretastatin A4 phosphate, combretastatin A4 and combretastatin A4 glucuronide in beagle dog plasma and its application to a pharmacokinetic study[J]. Chromatogr B Analyt Technol Biomed Life Sci,2009(877):3813-3822.
[13] He X, Li S, Huang H, et al. A pharmacokinetic and safety study of single dose intravenous combretastatin A4 phosphate in Chinese patients with refractory solid tumours[J]. Br J Clin Pharmacol,2011(71):860-870.