Biotransformation of [14C]dasatinib:: In vitro studies in rat, monkey, and human and disposition after administration to rats and monkeys
Biotransformation of [14C]dasatinib:: In vitro studies in rat, monkey, and human and disposition after administration to rats and monkeys
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DOI：
10.1124/dmd.107.018234
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发表时间：
2008-07-01
影响因子：
3.9
通讯作者：
Iyer, Ramaswamy A.
中科院分区：
文献类型：
--
作者：
Christopher, Lisa J.;Cui, Donghui;Iyer, Ramaswamy A.
本研究描述了[C-14]达沙替尼在大鼠、猴和人肝组织孵育中的体外代谢以及在大鼠和猴体内的代谢。跨物种，达沙替尼在体外进行氧化代谢，形成五种主要的氧化代谢物。在肝细胞孵育中，除初级代谢产物外，还观察到达沙替尼及其氧化代谢产物的氧化途径和结合代谢产物的结合形成的次级代谢产物。在对大鼠和猴子进行的体内研究中，大部分放射性剂量是从胆汁和粪便中排出的。在静脉注射后胆管插管的猴子。剂量，13.7%的放射性剂量是通过粪便直接分泌排出的。达沙替尼分别占大鼠和猴血浆总放射性曲线下面积(AUC)(0~8h)的56%和26%，而多种代谢产物分别占TRA曲线下面积(0~8h)的44%和74%。在大鼠和猴子的胆汁中，达沙替尼占排泄剂量的12%，这表明达沙替尼在消除之前被广泛代谢。胆汁的代谢谱与肝细胞的代谢谱相似。在这两个物种中，胆汁中排出的放射性很大一部分(=剂量的29%)归因于N-氧化物和结合代谢物。在大鼠和猴子的粪便中，只发现了氧化代谢物及其进一步的氧化产物。粪便中没有结合型或氮氧化物代谢物，说明在排泄之前，胃肠道中分别有水解物或还原物质。
This study describes the in vitro metabolism of [C-14]dasatinib in liver tissue incubations from rat, monkey, and human and the in vivo metabolism in rat and monkey. Across species, dasatinib underwent in vitro oxidative metabolism to form five primary oxidative metabolites. In addition to the primary metabolites, secondary metabolites formed from combinations of the oxidative pathways and conjugated metabolites of dasatinib and its oxidative metabolites were also observed in hepatocytes incubations. In in vivo studies in rats and monkeys, the majority of the radioactive dose was excreted in the bile and feces. In bile duct-cannulated monkeys after an i.v. dose, 13.7% of the radioactive dose was excreted in the feces through direct secretion. Dasatinib comprised 56 and 26% of the area under the curve (AUC) (0-8 h) of total radioactivity (TRA) in plasma, whereas multiple metabolites accounted for the remaining 44 and 74% of the AUC (0-8 h) of TRA for rats and monkeys, respectively. In rat and monkey bile, dasatinib accounted for < 12% of the excreted dose, suggesting that dasatinib was extensively metabolized before elimination. The metabolic profiles in bile were similar to the hepatocyte profiles. In both species, a large portion of the radioactivity excreted in bile (>= 29% of the dose) was attributed to N-oxides and conjugated metabolites. In rat and monkey feces, only the oxidative metabolites and their further oxidation products were identified. The absence of conjugative or N-oxide metabolites in the feces suggests hydrolysis or reduction, respectively, in the gastrointestinal tract before elimination.