Pharmacokinetics and tissue distribution model of cabozantinib in rat determined by UPLC–MS/MS

• A LC–MS determination method of cabozantinib in plasma and tissues was developed.
• The pharmacokinetic study of cabozantinib in rats was investigated.
• The distribution of cabozantinib in tissues was studied.
• A BP-ANN tissue distribution model of cabozantinib in rat was developed.

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 5–5000 ng/mL (r2 > 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, 10 mg/kg and ig 15, 30 mg/kg) revealed that XL184 was eliminated slowly, the t1/2 was longer than 10 h 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.