达沙替尼(BMS-354825)的临床前药代动力学和体外代谢:一种抗SRC和BCR-ABL的有效口服多靶向激酶抑制剂。

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王军，李飞，王志强，王志强

达沙替尼(BMS-354825)的临床前药代动力学和体外代谢:一种抗SRC和BCR-ABL的有效口服多靶向激酶抑制剂。

癌症化疗药物。2008 Mar;61(3):365-76。Epub 2007年4月11日。

PubMed ID

17429625 (PubMed视图

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摘要

目的:达沙替尼(BMS-354825)是一种抗SRC和BCR-ABL的强效口服多靶向激酶抑制剂，最近已被批准用于治疗慢性骨髓性白血病(CML)的伊马替尼获得性耐药和不耐受。在小鼠、大鼠、狗和猴子体内进行了达沙替尼的药代动力学和代谢的体外和体内研究。研究了达沙替尼在动物体内不完全口服生物利用度的可能机制。方法:用肝微粒体(NADPH-或udpga强化的)和分离的小鼠、大鼠、狗、猴和人肝细胞孵育后，测定达沙替尼的代谢稳定性。在所有情况下，测量底物随时间的消耗，并使用适当的比例因子来预测体内清除率。在单次静脉注射或口服给药后，测定达沙替尼在小鼠、大鼠、狗和猴子体内的药代动力学。此外，观察达沙替尼对胆管插管(BDC)大鼠的排泄途径。通过各种体外和体内模型，如Caco-2细胞、p -糖蛋白(P-gp)敲除小鼠和大鼠门静脉内给药，评估吸收和首过代谢是不完全口服生物利用度的可能原因。结果:达沙替尼在小鼠、大鼠、狗和猴体内系统血浆清除率分别为62、26、25和34 ml/min/kg。体外肝细胞和肝微粒体数据的缩放为所有物种的体内清除率提供了相当好的预测。 Percent distribution in blood cells ranged from 43% in mouse to 57% in dog. Dasatinib showed high volumes of distribution (>3 l/kg) and high serum protein binding values (>90%) in all four species tested. Oral bioavailability of dasatinib ranged from 14% in the mouse to 34% in the dog. In rats, bioavailability after an intraportal dose was comparable to that after intra-arterial administration. In BDC rats, less than 15% of an intravenous dose was excreted unchanged in urine, bile, and the gastrointestinal tract, suggesting that dasatinib is cleared primarily via metabolism. Dasatinib has high intrinsic permeability in Caco-2 cells, however, the efflux ratio was approximately two-fold indicating that it may be a substrate for an intestinal efflux transporter. However, in vivo studies in P-gp knockout mice versus wild-type mice showed no difference in the amount of dasatinib remaining unabsorbed in the gastrointestinal tract, suggesting that P-gp may not be responsible for the incomplete bioavailability. CONCLUSIONS: Dasatinib shows intermediate clearance in mouse, rat, dog, and monkey, and distributes extensively in those species. Oxidative metabolism appears to be the predominant clearance pathway. The incomplete oral bioavailability may be due to both incomplete absorption and high first-pass metabolism. However, the efflux transporter, P-glycoprotein does not appear to be limiting oral absorption.

引用本文的药物库数据

药物靶点

药物	目标	种类	生物	药理作用	行动
达沙替尼	原癌基因酪氨酸蛋白激酶	蛋白质	人类	是的	多目标	细节