Studies on the disposition of 2,3-dihydro-1H-imidazo [1,2-b] pyrazole in rodents

D.Dale Shoemaker, Ovella C. Ayers, Mary Ellen D'Anna, Richard L. Cysyk
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引用次数: 3

Abstract

2,3-Dihydro-1H-imidazo [1,2-b] pyrazole (IMPY, NSC-51143) is a new ribonucleotide reductase inhibitor, presently undergoing clinical evaluation, that exhibits prolonged in vivo antitumor activity in experimental animals. Disposition studies were initiated to determine if the prolonged in vivo antitumor activity of IMPY could be explained by its pharmacologic properties. Plasma disappearance curves of radioactivity were biphasic after the i.v. administration of 100, 250 or 500 mg/kg to rats and 250 mg/kg to mice. The distribution phase was rapid in each case (t12 of approximately 30 min or less), followed by a prolonged elimination phase. Radioactivity was distributed to all tissues of rats and mice including brain after an i.v. dose of 250 mg/kg. In rats, 67.8% of the administered radioactivity was excreted in the urine during the first 24 hr. By 120 hr 74.3% had been excreted via the urine compared with 11.1% in the fees, the latter by biliary excretion. The chromatographic profile of the urine collected from rats and mice 4 hr after drug administration indicated extensive metabolism. Thus, the prolonged plasma and tissue levels of parent IMPY and its metabolites can account for the prolonged duration of cytotoxic activity in vivo.

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2,3-二氢- 1h -咪唑[1,2-b]吡唑在啮齿动物体内的分布研究
2,3-二氢- 1h -咪唑[1,2-b]吡唑(IMPY, NSC-51143)是一种新的核糖核苷酸还原酶抑制剂,目前正在进行临床评估,在实验动物中显示出持久的体内抗肿瘤活性。为了确定IMPY体内抗肿瘤活性的延长是否可以用它的药理学特性来解释,研究人员开始了处置研究。大鼠静脉给药100、250、500 mg/kg,小鼠静脉给药250 mg/kg,血浆放射性消失曲线呈双相变化。每个病例的分配阶段都很迅速(大约30分钟或更短),随后是一个延长的消除阶段。静脉注射剂量为250 mg/kg后,放射性分布到大鼠和小鼠的所有组织,包括脑。在大鼠中,67.8%的放射性物质在前24小时随尿液排出。到120小时时,74.3%通过尿液排泄,而费用为11.1%,后者通过胆道排泄。给药后4小时收集的大鼠和小鼠尿液的色谱图谱显示广泛的代谢。因此,母体IMPY及其代谢物的血浆和组织水平的延长可以解释体内细胞毒性活性持续时间的延长。
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