PLASMA PHARMACOKINETICS OF THE ANTITUMOR AGENTS 5,6-DIMETHYLXANTHENONE-4-ACETIC ACID, XANTHENONE-4-ACETIC ACID AND FLAVONE-8-ACETIC ACID IN MICE
PLASMA PHARMACOKINETICS OF THE ANTITUMOR AGENTS 5,6-DIMETHYLXANTHENONE-4-ACETIC ACID, XANTHENONE-4-ACETIC ACID AND FLAVONE-8-ACETIC ACID IN MICE
复制标题
DOI：
10.1007/bf00685815
复制
发表时间：
1991-01-01
影响因子：
3
通讯作者：
BAGULEY, BC
中科院分区：
文献类型：
--
作者：
MCKEAGE, MJ;KESTELL, P;BAGULEY, BC
虽然抗肿瘤剂黄酮-8-乙酸（FAA）对小鼠实体瘤表现出显著的活性，但其临床使用具有许多药理学缺点，包括低剂量效力和剂量依赖性药代动力学。在寻找FAA类似物的过程中，合成了咕吨酮-4-乙酸（XAA）及其5，6-二甲基衍生物（5，6-MeXAA）。5，6-MeXAA、XAA和FAA在BDF（1）小鼠中的最大耐受剂量（MTD）分别为99、1，090和1，300 μ mol/kg。在MTD时，5，6-MeXAA表现出以下药代动力学特性：最大血浆浓度，600 μ M;平均滞留时间，4.9小时; AUC，2，400 μ mol h l-1;稳态分布容积，0.2 l/kg。所有化合物在MTD时均显示非线性消除动力学，但当AUC的对数相对于递送剂量的对数作图时，发现5，6-MeXAA的回归线斜率为1.2，而XAA为1.4，FAA为1.98。因此，5，6-MeXAA仅显示出与剂量非依赖性动力学的轻微偏离。5，6-MeXAA与血浆蛋白的结合方式与FAA相似，但前者游离药物的血浆浓度低于后者。因此，计算的血浆中5，6-MeXAA的最大游离药物浓度比FAA低23倍。
Although the antitumour agent flavone-8-acetic acid (FAA) exhibits remarkable activity against murine solid tumours, its clinical use has a number of pharmacological drawbacks, including low dose potency and dose-dependent pharmacokinetics. Xanthenone-4-acetic acid (XAA) and its 5,6-dimethyl derivative (5,6-MeXAA) were synthesised during a search for better analogues of FAA. The maximal tolerated doses (MTDs) of 5,6-MeXAA, XAA and FAA in BDF(l) mice were 99, 1,090 and 1,300-mu-mol/kg, respectively. At the MTD, 5,6-MeXAA displayed the following pharmacokinetic properties: maximal plasma concentration, 600-mu-M; mean residence time, 4.9 h; AUC, 2,400-mu-mol h l-1; and volume of steady-state distribution, 0.2 l/kg. All compounds displayed nonlinear elimination kinetics at the MTD, but when the logarithm of the AUC was plotted against that of the delivered dose, the slope of the regression line for 5,6-MeXAA was found to be 1.2 as opposed to 1.4 for XAA and 1.98 for FAA. 5,6-MeXAA thus showed only a slight deviation from dose-independent kinetics. 5,6-MeXAA bound to plasma proteins in a manner similar to that exhibited by FAA, although the plasma concentration of free drug was lower for the former than for the latter. As a consequence, the calculated maximal free drug concentration for 5,6-MeXAA in plasma was 23 times lower than that for FAA.