title: Liquid Chromatography-Mass Spectrometry/Mass Spectrometry Analysis and Pharmacokinetic Assessment of Ponatinib in Sprague-Dawley Rats.
abstract: BACKGROUND
  By means of liquid-liquid extraction with ethyl acetate, a rapid, sensitive, and specific LC-MS/MS method was developed and validated for assaying ponatinib and the internal standard, warfarin.
  
  
  METHODS
  The method was verified and successfully applied to evaluate the pharmacokinetics of ponatinib in Sprague-Dawley rats.
  
  
  RESULTS
  Ponatinib showed dose-dependent exposure in the circulation system, and the absolute bioavailabilities of ponatinib were 43.95 ± 2.40%, 47.69 ± 5.08% and 55.02 ± 2.50% after intragastric administration of 7.5, 15.0 and 30.0 mg/kg ponatinib in rats, respectively. After consecutive administration at 3.75 mg/kg for 7 days, there was distinct accumulation of ponatinib (AUC0-∞= 5479.41 ± 757.07 μg h/L) relative to that of a single dose (AUC0-∞= 2301.84 ± 787.10 μg h/L,p< 0.05), and the MRT increased from 16.77 ± 1.91 to 21.34 ± 1.27 h (p< 0.05). Analysis of ponatinib in various tissues revealed it was distributed widely in the body, highly exposed in the lung, thyroid, and lowly exposed in plasma, the brain, bone and the liver, indicating its potential action on lung cancer with lower system toxicity. Ponatinib was eliminated primarily in feces at 26.17 ± 7.70% of its original form and only 0.24 ± 0.10% in urine.
  
  
  CONCLUSIONS
  For the first time, the pharmacokinetics of ponatinib were systematically evaluated in rats, which facilitated the study and development of the analogous candidates of ponatinib.
authors.affiliation: Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.affiliation: Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.affiliation: ChongQing Huapont Pharm. Co., Ltd., Chongqing, China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Fei
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, China.
authors.forename: Shuyao
authors.initials: S
authors.lastname: Wang
authors.affiliation: Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.
authors.forename: Siqi
authors.initials: S
authors.lastname: Feng
authors.affiliation: Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.
authors.forename: Jingqiu
authors.initials: J
authors.lastname: Huang
authors.affiliation: Pharmacy School, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Wang
authors.affiliation: Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.
authors.forename: Jiye
authors.initials: J
authors.lastname: Aa
authors.affiliation: Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
keywords: Excretion; LC–MS/MS; Pharmacokinetics; Ponatinib; TKIs; Tissue distribution