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Pharmacokinetics and tissue distribution model of cabozantinib in rat determined by UPLC-MS/MS
Xianqin Wang1, Shuanghu Wang2, Feiyan Lin3
1Analytical and Testing Center, Wenzhou Medical University, 325035 Wenzhou, China.
Abstract:
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.
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