Disposition in mice of 7-hydroxystaurosporine, a protein kinase inhibitor with antitumor activity.
Disposition in mice of 7-hydroxystaurosporine, a protein kinase inhibitor with antitumor activity.
复制标题
7-羟基星形孢菌素（一种具有抗肿瘤活性的蛋白激酶抑制剂）在小鼠体内的分布。
DOI：
10.1007/bf00686290
复制
发表时间：
1994
影响因子：
3
通讯作者：
Posey,CF
中科院分区：
文献类型：
--
作者：
Hill,DL;Tillery,KF;Rose,LM;Posey,CF
UCN-01是星形孢菌素的羟基化衍生物，由于其具有良好的抗肿瘤活性而被选择用于研究。对于静脉内、皮下或通过口服管饲给予该化合物的小鼠，最大耐受剂量（MTD）分别为20、10和>100 mg/kg。UCN-01在小鼠和犬血浆中稳定，但在人血浆中，其在不受标准蛋白酶和酯酶抑制剂抑制的过程中转化为代谢产物。静脉给予10 mg/kg UCN-01后，初始（t1/2α）和终末（t1/2β）消除指数相的半衰期分别为10和85 min;血浆浓度-时间曲线下面积（AUC值）为117 μg min ml−1。在经口灌胃给予10 mg/kg的小鼠中，消除相半衰期的计算值为150 min。AUC值为15 μg min ml−1，生物利用度为13%。以10 mg/kg皮下给药后，分布和消除相的半衰期计算值分别为23和130 min; AUC值为113 μg min ml−1。由于该值与静脉给药获得的值相当，因此通过皮下途径给予UCN-01可能是临床前和临床试验中静脉给药的替代方案。
UCN-01, a hydroxylated derivative of staurosporine, was selected for study because of its promising antitumor activity. For mice dosed intravenously, subcutaneously, or by oral gavage with this compound, the maximum tolerated doses (MTD) were 20, 10, and >100 mg/kg, respectively. UCN-01 was stable in mouse and dog plasma, but in human plasma it was converted to a metabolite in a process not inhibited by standard protease and esterase inhibitors. Following n intravenous dose of 10 mg/kg UCN-01, the half-lives for the initial (t1/2α) and terminal (t1/2β) exponential phases of elimination were 10 and 85 min, respectively; the area under the plasma concentration-time curve (AUC value) was 117 μg min ml−1. In mice dosed by oral gavage with 10 mg/kg, the calculated value for the half-life of the elimination phase was 150 min. The AUC value was 15 μg min ml−1, giving a value for bioavailability of 13%. After subcutaneous dosing with 10 mg/kg, the calculated values for half-lives for the distribution and elimination phases were 23 and 130 min, respectively; the AUC value was 113 μg min ml−1. Since this value is equivalent to that obtained for intravenous dosing, administration of UCN-01 by the subcutaneous route may be an alternative to intravenous dosing in preclinical and clinical trials.