Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; Analytical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St, Cairo 11562, Egypt.
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Clin Chim Acta. 2018 Oct;485:144-151. doi: 10.1016/j.cca.2018.06.035. Epub 2018 Jun 30.
Ponatinib (Iclusig®) is a multi-targeted tyrosine kinase inhibitor (TKIs). It is active against T315I and other BCR-ABL mutants. Investigation of in vivo metabolism of ponatinib was done using Sprague Dawley rats by giving one oral dose of PNT (4.7 mg/kg) to each rat and urine samples were gathered at several time intervals from dosing. Filteration of urine samples was done through 0.45 μm syringe filters. Phase separation using ACN was applied for extraction of ponatinib related metabolites. Characterization and identification of one in vivo phase II metabolite and thirteen in vivo phase I of PNT were done using LC-MS/MS. Phase I metabolic reactions were reduction, N-demethylation, hydroxylation, N-oxidation, oxidation and amide hydrolysis. Phase II metabolic reaction was glucuronidation of hydroxyl benzyl metabolites of ponatinib. The major in vivo metabolic reactions were α hydroxylation and α oxidation at piperazine ring. Literature review revealed no articles that have been published on in vivo metabolism of ponatinib in Sprague Dawley rats or ponatinib in vivo phase I and phase II metabolites structural characterization and identification.
泊那替尼（Iclusig®）是一种多靶点酪氨酸激酶抑制剂（TKI）。它对 T315I 和其他 BCR-ABL 突变体具有活性。通过给予每只大鼠口服泊那替尼（4.7mg/kg），在 Sprague Dawley 大鼠体内进行了泊那替尼的体内代谢研究，并在给药后的几个时间点收集尿液样本。通过 0.45μm 注射器过滤器对尿液样本进行过滤。使用 ACN 进行相分离，以提取泊那替尼相关代谢物。使用 LC-MS/MS 对一种体内 II 相代谢物和 13 种体内 I 相 PNT 进行了表征和鉴定。I 相代谢反应为还原、N-去甲基化、羟化、N-氧化、氧化和酰胺水解。II 相代谢反应是泊那替尼羟基苄基代谢物的葡萄糖醛酸化。体内主要的代谢反应是哌嗪环的α-羟化和α-氧化。文献综述显示，尚未有关于泊那替尼在 Sprague Dawley 大鼠体内的代谢或泊那替尼体内 I 相和 II 相代谢物结构表征和鉴定的文章发表。
