帕唑帕尼在大鼠体内药动学研究

周陈建; 赵嫏嬛; 胡国新

doi:10.3969/j.issn.1006-0111.2017.04.014

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帕唑帕尼在大鼠体内药动学研究

周陈建, 赵嫏嬛, 胡国新

文章导航 > 药学实践与服务 > 2017 > 35(4): 346-349

周陈建, 赵嫏嬛, 胡国新. 帕唑帕尼在大鼠体内药动学研究[J]. 药学实践与服务, 2017, 35(4): 346-349. doi: 10.3969/j.issn.1006-0111.2017.04.014

引用本文:

周陈建, 赵嫏嬛, 胡国新. 帕唑帕尼在大鼠体内药动学研究[J]. 药学实践与服务, 2017, 35(4): 346-349. doi: 10.3969/j.issn.1006-0111.2017.04.014

ZHOU Chenjian, ZHAO Langhuan, HU Guoxin. Study on pharmacokinetics of pazopanib in rats[J]. Journal of Pharmaceutical Practice and Service, 2017, 35(4): 346-349. doi: 10.3969/j.issn.1006-0111.2017.04.014

Citation:

ZHOU Chenjian, ZHAO Langhuan, HU Guoxin. Study on pharmacokinetics of pazopanib in rats[J]. Journal of Pharmaceutical Practice and Service, 2017, 35(4): 346-349. doi: 10.3969/j.issn.1006-0111.2017.04.014

帕唑帕尼在大鼠体内药动学研究

doi: 10.3969/j.issn.1006-0111.2017.04.014

1.
温州市中心医院, 浙江温州 325000
2.
温州市人民医院, 浙江温州 325000
3.
温州市医科大学, 浙江温州 325000

Study on pharmacokinetics of pazopanib in rats

1.
Center Hospital of Wenzhou, Wenzhou 235000, China
2.
People's Hospital of Wenzhou, Wenzhou 235000, China
3.
Medical College of Wenzhou, Wenzhou 235000, China

摘要: 目的建立大鼠血浆中检测帕唑帕尼的超高效液相色谱-质谱（UPLC-MS）的方法，研究帕唑帕尼在大鼠体内的药动学过程。方法大鼠血浆样品用乙腈沉淀后检测。采用Acquity U-HPLC BEH C₁₈柱为分离柱，流动相采用乙腈-0.1%甲酸体系，梯度洗脱；采用AB Sciex QTRAP 5500三重四级杆质谱仪（电喷雾离子源）进行质谱检测，帕唑帕尼和内标地西泮采用多反应监测（MRM）的方法检测，帕唑帕尼和内标地西泮（ISTD）的MRM分别为m/z 438.3→357.2 和 m/z 285.2→193.1；雄性SD大鼠6只，灌胃给予80 mg/kg 帕唑帕尼，在给药前和给药后的不同时间点于大鼠尾静脉取血。用建立的方法测定血浆中帕唑帕尼的浓度。用DAS 3.0计算主要药动学参数。结果大鼠血浆中帕唑帕尼浓度在0.25~40.00 μg/ml范围内线性关系良好（r=0.999 2）；低、中、高3个质量浓度（0.50、10.00、30.00 μg/ml）的日内精密度RSD分别为6.17%、2.73%和2.54 %，日间精密度RSD分别为7.56%、5.98%和2.84%，回收率分别为（78.4±4.8）%、（85.9±3.5）%和（81.1±4.2）%，基质效应分别为（106.7±5.3）%、（101.3±6.7）%和（97.6±4.4）%；血浆帕唑帕尼的主要药动学参数：峰值浓度c_max为（20.22±1.95）μg/ml，达峰时间t_max为（1.75±0.76）h，半衰期t_1/2为（7.35±2.31）h，药-时曲线下面积AUC_0-t为（213.16±39.92）μg·h/L，AUC_0-∞为（215.79±39.84）μg·h/L，表观分布容积Vd为（4.10±1.78）L/kg，清除率CL为（0.38±0.07）L/h。用房室模型拟合，帕唑帕尼在大鼠体内呈一级消除的二室模型。结论本研究建立用UPLC-MS检测大鼠血浆帕唑帕尼的方法，专属性高，分离完全，检测时间短；适合帕唑帕尼的药动学和药物相互作用研究。
- 帕唑帕尼 /
- 超高效液相色谱-质谱 /
- 药动学
Abstract: Objective To develop a UPLC-MS method for the determination of pazopanib in rat plasma, and study the pharmacokinetics of pazopanib in rats. Methods The effective UPLC MS/MS separation of the examined compounds was applied on an Acquity BEH C₁₈ column with a gradient mobile phase system. AB Sciex QTRAP 5500 triple quadruple mass spectrometer equipped with an electrospray ionization (ESI) interface was used for mass spectrometric detection. The MRM transitions of m/z 438.3→357.2 and m/z 285.2→193.1 were used to quantify for pazopanib and ISTD, respectively; 6 rats were given 80 mg/kg pazopanib intragastric administration. Blood samples were collected from the tail vein at different point after administration. The concentration of pazopanib in plasma was detected by the UPLC-MS methods. The pharmacokinetics parameters were analyzed by DAS program. Results Pazopanib and ISTD were eluted at 1.10 and 1.37 min respectively. Excellent liner relationship was obtained from the range of 0.25 μg/ml to 40.00 μg/ml (r=0.999 2). The intra-day RSD were 6.17%, 2.73% and 2.54% and inter-day RSD were 7.56%, 5.98% and 2.84% respectively at three concentrations (0.50, 10.00, 30.00 μg/ml), the recoveries were (78.4±4.8)%, (85.9±3.5)% and (81.1±4.2)% respectively, the Matrix effect were (106.7±5.3) %, (101.3±6.7) % and (97.6±4.4) % respectively at three concentrations (0.50, 10.00, 30.00 μg/ml); 6 rats were given 80 mg/kg pazopanib intra-gastric administration. The main pharmacokinetics parameters of pazopanib were as following: c_max (20.22±1.95) μg/ml,t_max (1.75±0.76) h,t_1/2 (7.35±2.31) h,AUC_0-t (213.16±39.92) μg·h/L,AUC_0-∞ (215.79±39.84) μg·h/L,Vd (4.10±1.78) L/kg,CL (0.38±0.07) L/h. Conclusion The method was simple, rapid, accurately,which could be used to determine the pazopanib concentration in rat plasma and study on its pharmacokinetics. Pazopanib was fitted to the first-order elimination kinetics in rats.
- pazopanib /
- UPLC-MS /
- pharmacokinetics

[1]	Ranieri G, Mammì M, Donato Di Paola E,et al. Pazopanib a tyrosine kinase inhibitor with strong anti-angiogenetic activity: A new treatment for metastatic soft tissue sarcoma[J]. Crit Rev Oncol Hematol,2014,89(2):322-329.
[2]	Hamberg P, Verweij J, Sleijfer S. (Pre-)clinical pharmacology and activity of pazopanib, a novel multikinase angiogenesis inhibitor[J].Oncologist,2010,15(6):539-547.
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帕唑帕尼在大鼠体内药动学研究

doi: 10.3969/j.issn.1006-0111.2017.04.014

1. 温州市中心医院, 浙江温州 325000

2. 温州市人民医院, 浙江温州 325000

3. 温州市医科大学, 浙江温州 325000

收稿日期: 2016-12-19
修回日期: 2017-02-17

关键词:

帕唑帕尼 /

超高效液相色谱-质谱 /

药动学

摘要: 目的建立大鼠血浆中检测帕唑帕尼的超高效液相色谱-质谱（UPLC-MS）的方法，研究帕唑帕尼在大鼠体内的药动学过程。方法大鼠血浆样品用乙腈沉淀后检测。采用Acquity U-HPLC BEH C₁₈柱为分离柱，流动相采用乙腈-0.1%甲酸体系，梯度洗脱；采用AB Sciex QTRAP 5500三重四级杆质谱仪（电喷雾离子源）进行质谱检测，帕唑帕尼和内标地西泮采用多反应监测（MRM）的方法检测，帕唑帕尼和内标地西泮（ISTD）的MRM分别为m/z 438.3→357.2 和 m/z 285.2→193.1；雄性SD大鼠6只，灌胃给予80 mg/kg 帕唑帕尼，在给药前和给药后的不同时间点于大鼠尾静脉取血。用建立的方法测定血浆中帕唑帕尼的浓度。用DAS 3.0计算主要药动学参数。结果大鼠血浆中帕唑帕尼浓度在0.25~40.00 μg/ml范围内线性关系良好（r=0.999 2）；低、中、高3个质量浓度（0.50、10.00、30.00 μg/ml）的日内精密度RSD分别为6.17%、2.73%和2.54 %，日间精密度RSD分别为7.56%、5.98%和2.84%，回收率分别为（78.4±4.8）%、（85.9±3.5）%和（81.1±4.2）%，基质效应分别为（106.7±5.3）%、（101.3±6.7）%和（97.6±4.4）%；血浆帕唑帕尼的主要药动学参数：峰值浓度c_max为（20.22±1.95）μg/ml，达峰时间t_max为（1.75±0.76）h，半衰期t_1/2为（7.35±2.31）h，药-时曲线下面积AUC_0-t为（213.16±39.92）μg·h/L，AUC_0-∞为（215.79±39.84）μg·h/L，表观分布容积Vd为（4.10±1.78）L/kg，清除率CL为（0.38±0.07）L/h。用房室模型拟合，帕唑帕尼在大鼠体内呈一级消除的二室模型。结论本研究建立用UPLC-MS检测大鼠血浆帕唑帕尼的方法，专属性高，分离完全，检测时间短；适合帕唑帕尼的药动学和药物相互作用研究。

English Abstract

Study on pharmacokinetics of pazopanib in rats

1. Center Hospital of Wenzhou, Wenzhou 235000, China

2. People's Hospital of Wenzhou, Wenzhou 235000, China

3. Medical College of Wenzhou, Wenzhou 235000, China

Received Date: 2016-12-19
Rev Recd Date: 2017-02-17

Keywords:

Abstract: Objective To develop a UPLC-MS method for the determination of pazopanib in rat plasma, and study the pharmacokinetics of pazopanib in rats. Methods The effective UPLC MS/MS separation of the examined compounds was applied on an Acquity BEH C₁₈ column with a gradient mobile phase system. AB Sciex QTRAP 5500 triple quadruple mass spectrometer equipped with an electrospray ionization (ESI) interface was used for mass spectrometric detection. The MRM transitions of m/z 438.3→357.2 and m/z 285.2→193.1 were used to quantify for pazopanib and ISTD, respectively; 6 rats were given 80 mg/kg pazopanib intragastric administration. Blood samples were collected from the tail vein at different point after administration. The concentration of pazopanib in plasma was detected by the UPLC-MS methods. The pharmacokinetics parameters were analyzed by DAS program. Results Pazopanib and ISTD were eluted at 1.10 and 1.37 min respectively. Excellent liner relationship was obtained from the range of 0.25 μg/ml to 40.00 μg/ml (r=0.999 2). The intra-day RSD were 6.17%, 2.73% and 2.54% and inter-day RSD were 7.56%, 5.98% and 2.84% respectively at three concentrations (0.50, 10.00, 30.00 μg/ml), the recoveries were (78.4±4.8)%, (85.9±3.5)% and (81.1±4.2)% respectively, the Matrix effect were (106.7±5.3) %, (101.3±6.7) % and (97.6±4.4) % respectively at three concentrations (0.50, 10.00, 30.00 μg/ml); 6 rats were given 80 mg/kg pazopanib intra-gastric administration. The main pharmacokinetics parameters of pazopanib were as following: c_max (20.22±1.95) μg/ml,t_max (1.75±0.76) h,t_1/2 (7.35±2.31) h,AUC_0-t (213.16±39.92) μg·h/L,AUC_0-∞ (215.79±39.84) μg·h/L,Vd (4.10±1.78) L/kg,CL (0.38±0.07) L/h. Conclusion The method was simple, rapid, accurately,which could be used to determine the pazopanib concentration in rat plasma and study on its pharmacokinetics. Pazopanib was fitted to the first-order elimination kinetics in rats.