临床前药物动力学和体外代谢的达沙替尼(bms - 354825):一个强有力的口服多靶向对SRC和bcr - abl激酶抑制剂。

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Kamath AV,王J,李财政年度,Marathe PH

临床前药物动力学和体外代谢的达沙替尼(bms - 354825):一个强有力的口服多靶向对SRC和bcr - abl激酶抑制剂。

癌症Chemother杂志。2008年3月,61 (3):365 - 76。Epub 2007年4月11日。

PubMed ID

17429625 (在PubMed

]

文摘

目的:达沙替尼(bms - 354825),一个强有力的口服多靶向激酶抑制剂对SRC和bcr - abl,最近被批准用于治疗慢性粒细胞性白血病(CML) imatinib-acquired阻力和不宽容。体外和体内的研究进行的药物动力学和代谢达沙替尼的老鼠,老鼠,狗和猴子。可能机制导致动物达沙替尼的不完整的口服生物利用度。方法:达沙替尼的代谢稳定性测定孵化后肝微粒体(NADPH -或UDPGA-fortified)和孤立肝细胞从老鼠,鼠,狗,猴子,和人类。在所有情况下,随着时间的推移衬底损耗测量,和适当的缩放因子被用来预测体内清除。药物动力学的达沙替尼决定在小鼠、大鼠、狗和猴子经过政府的单一静脉或口服剂量。此外,排泄后被调查政府的路线的达沙替尼胆管插管(BDC)老鼠。尽可能的吸收和初步的代谢评估不完整的口服生物利用度的原因使用各种体外和体内模型像Caco-2细胞,22 (P-gp)基因敲除小鼠,intra-portal老鼠体内剂量。结果:体内系统等离子体间隙值的达沙替尼62年,26岁,25岁和34毫升/分钟/公斤的老鼠,老鼠,狗和猴子。体外肝细胞和肝微粒体数据的扩展了相当不错的预测体内所有物种的许可。 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.

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药物靶点

药物	目标	类	生物	药理作用	行动
达沙替尼	原癌基因酪氨酸受体激酶Src	蛋白质	人类	是的	抑制剂 多目标	细节