title: Pharmacokinetics and tissue distribution model of cabozantinib in rat determined by UPLC-MS/MS.
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.
authors: Analytical and Testing Center, Wenzhou Medical University, 325035 Wenzhou, China.
authors: Xianqin
authors: X
authors: Wang
authors: The Laboratory of Clinical Pharmacy, People's Hospital of Lishui City, 323000 Lishui, China.
authors: Shuanghu
authors: S
authors: Wang
authors: The First Affiliated Hospital of Wenzhou Medical University, 325035 Wenzhou, China.
authors: Feiyan
authors: F
authors: Lin
authors: Shanghai Institute of Pharmaceutical Industry, 200437 Shanghai, China.
authors: Qingwei
authors: Q
authors: Zhang
authors: College of Physics and Electronic Information Engineering, Wenzhou University, 325035 Wenzhou, China.
authors: HuiLing
authors: H
authors: Chen
authors: Analytical and Testing Center, Wenzhou Medical University, 325035 Wenzhou, China.
authors: Xianchuan
authors: X
authors: Wang
authors: Analytical and Testing Center, Wenzhou Medical University, 325035 Wenzhou, China.
authors: Congcong
authors: C
authors: Wen
authors: Analytical and Testing Center, Wenzhou Medical University, 325035 Wenzhou, China.
authors: Jianshe
authors: J
authors: Ma
authors: The First Affiliated Hospital of Wenzhou Medical University, 325035 Wenzhou, China. Electronic address: hulufeng79@sina.com.
authors: Lufeng
authors: L
authors: Hu
mesh_terms: D000813:Anilides / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D002138:Calibration; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004355:Drug Stability; D008099:Liver / Q000378:metabolism; D008874:Midazolam / Q000737:chemistry; D016571:Neural Networks, Computer; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry / Q000379:methods*; D014018:Tissue Distribution
chemical_list: D000813:Anilides; D011725:Pyridines; C558660:cabozantinib; D008874:Midazolam
keywords: BP-ANN; Cabozantinib; Pharmacokinetics; UPLC–MS/MS