Altered irinotecan and SN-38 disposition after intravenous and oral administration of irinotecan in mice bearing human neuroblastoma xenografts.
Altered irinotecan and SN-38 disposition after intravenous and oral administration of irinotecan in mice bearing human neuroblastoma xenografts.
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发表时间：
1998-02
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通讯作者：
W. Zamboni;P. Houghton;J. Thompson;P. Cheshire;S. Hanna;L. Richmond;X. Lou;C. Stewart
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作者：
W. Zamboni;P. Houghton;J. Thompson;P. Cheshire;S. Hanna;L. Richmond;X. Lou;C. Stewart
伊立替康体外抗肿瘤活性主要是由于其羧酸酯酶水解成活性代谢物SN-38。本研究旨在评价人神经母细胞瘤异种移植物对伊立替康静脉注射和口服伊立替康后对伊立替康和SN-38的影响。非荷瘤小鼠和携带三种不同人类神经母细胞瘤异种移植系（NB1691、NB1643和NBEB）的小鼠通过尾静脉短静脉注射或灌胃给予伊立替康（10 mg/kg）。获得一系列血浆样品，处理分离伊立替康和SN-38内酯，并用敏感和特异的高效液相色谱法进行检测。进行了非区室和区室药代动力学分析。采用四室模型分析伊立替康和SN-38静脉给药后的浓度-时间数据。与非肿瘤小鼠相比，携带神经母细胞瘤的小鼠在静脉注射和口服伊立替康后，肿瘤的存在增加了全身暴露量（1.2-3.8倍；P < 0.05）。此外，携带人类神经母细胞瘤的小鼠的全身SN-38暴露量比未携带肿瘤的小鼠高（1.3-3.8倍；P < 0.05），口服伊立替康后效果最大。提出了一个示意图模型，为我们的观察提供了一个机制基础。这些结果强调需要进行临床前药代动力学研究来评估肿瘤对药物处置的影响。
The antitumor activity of irinotecan in vitro primarily results from its hydrolysis by carboxylesterase to the active metabolite SN-38. The present study was conducted to evaluate the effect of human neuroblastoma xenografts on irinotecan and SN-38 disposition after i.v. and oral irinotecan administration. Non-tumor-bearing mice and mice bearing three different human neuroblastoma xenograft lines (NB1691, NB1643, and NBEB) were given irinotecan (10 mg/kg) by short i.v. injection into the tail vein or by oral gavage. Serial plasma samples were obtained, processed to isolate irinotecan and SN-38 lactone, and assayed with a sensitive and specific high-performance liquid chromatography assay. Noncompartmental and compartmental pharmacokinetic analyses were performed. A four-compartment model was used for analysis of irinotecan and SN-38 concentration-time data after i.v. administration. The presence of tumor increased irinotecan systemic exposure (1.2-3.8-fold; P < 0.05) after i.v. and oral administration in mice bearing neuroblastoma xenografts compared to non-tumor-bearing mice. Moreover, SN-38 systemic exposures were higher (1.3-3.8-fold; P < 0.05) in mice bearing human neuroblastoma xenografts as compared to non-tumor-bearing mice, with the greatest effect observed after oral administration of irinotecan. A schematic model is presented to provide a mechanistic basis for our observations. These results emphasize the need to perform preclinical pharmacokinetic studies to evaluate the influence of tumor on drug disposition.