Wang Xianqin, Wang Shuanghu, Lin Feiyan, Zhang Qingwei, Chen HuiLing, Wang Xianchuan, Wen Congcong, Ma Jianshe, Hu Lufeng
Analytical and Testing Center, Wenzhou Medical University, 325035 Wenzhou, China.
The Laboratory of Clinical Pharmacy, People's Hospital of Lishui City, 323000 Lishui, China.
J Chromatogr B Analyt Technol Biomed Life Sci. 2015 Mar 1;983-984:125-31. doi: 10.1016/j.jchromb.2015.01.020. Epub 2015 Jan 22.
Cabozantinib (XL184) is a novel small molecule inhibitor of receptor tyrosine kinases (RTKs) targeted at mesenchymal-epithelial transition factor (MET). In order to study the pharmacokinetics and tissue distribution in rat, a specific ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed with midazolam as internal standard. The calibration curves in plasma and tissues were linear in the range of 5-5000ng/mL (r(2)>0.99). The recoveries were better than 80.4% and matrix effects ranged from 96.9% to 105.1%. Then, the developed UPLC-MS/MS method was applied to determine the concentration of XL184 in blood and tissues. The pharmacokinetics of four different dosages (iv 5, 10mg/kg and ig 15, 30mg/kg) revealed that XL184 was eliminated slowly, the t1/2 was longer than 10h and the absolute bioavailability was 25.6±8.3%. The concentration distribution of XL184 in tissues was liver>lung>kidney>spleen>heart. Based on the concentration-time of XL184 in tissues, a BP-ANN distribution model was developed with good performance, and can be used to predict the concentration of XL184 in tissues.
卡博替尼（XL184）是一种新型的受体酪氨酸激酶（RTK）小分子抑制剂，作用靶点为间充质上皮转化因子（MET）。为研究其在大鼠体内的药代动力学和组织分布，以咪达唑仑为内标建立了一种特定的超高效液相色谱 - 串联质谱（UPLC - MS/MS）方法。血浆和组织中的校准曲线在5 - 5000ng/mL范围内呈线性（r(2)>0.99）。回收率优于80.4%，基质效应范围为96.9%至105.1%。然后，将所建立的UPLC - MS/MS方法应用于测定血液和组织中XL184的浓度。四种不同剂量（静脉注射5、10mg/kg和灌胃15、30mg/kg）的药代动力学研究表明，XL184消除缓慢，t1/2超过10小时，绝对生物利用度为25.6±8.3%。XL184在组织中的浓度分布为肝脏>肺>肾脏>脾脏>心脏。基于XL184在组织中的浓度 - 时间数据，建立了性能良好的BP - ANN分布模型，可用于预测组织中XL184的浓度。
