Effect of modulators of the multidrug resistance pump on the distribution of vinblastine in tissues of the mouse
Effect of modulators of the multidrug resistance pump on the distribution of vinblastine in tissues of the mouse
复制标题
多药耐药泵调节剂对长春花碱在小鼠组织中分布的影响
DOI：
10.1097/00001813-199601000-00007
复制
发表时间：
1996
影响因子：
2.3
通讯作者：
W. Stein
中科院分区：
文献类型：
--
作者：
E. Lyubimov;L. Lan;Irina Pashinsky;W. Stein
腹膜内施用剂量范围为0.2至6mg/kg体重的长春花碱。在不存在或存在药物 PSC 833、环孢菌素 A、甲氟喹、奎尼丁和双嘧达莫的情况下对小鼠进行实验，这些化合物均能调节多药耐药泵，从而增加细胞培养物中耐药细胞中这种细胞毒素的积累。在没有调节剂的情况下，长春花碱会不同程度地在组织中积累——大脑中最多，胰腺和肠道中最高。蓄积程度与长春花碱剂量成正比，剂量范围为 0.2-6 mg/kg 体重。无论是高剂量还是低剂量的长春碱，除奎尼丁外的所有调节剂均可将肝脏、肾脏、肠和肺积累长春碱的能力增加高达 5 倍，并且除甲氟喹外，还增加了胰腺中长春碱的水平。只有双嘧达摩尔对大脑也有显着影响。环孢菌素 A 有效增加了长春花碱的组织分布，其血浆浓度与细胞培养物中的细胞中阻断多药泵所需的浓度相似。对于甲氟喹，体内需要的血浆浓度是细胞培养中有效浓度的三到四倍。该小鼠系统提供了一种快速可靠的体内方法，可以在临床测试之前对调节剂进行测定。
Vinblastine at doses ranging from 0.2 to 6 mg/kg body weight was administered I.p. to mice in the absence or presence of the drugs PSC 833, cyclosporin A, mefloquine, quinidine and dipyridamole, all compounds that modulate the multidrug resistance pump and thus increase the accumulation of this cytotoxin in drug-resistant cells in cell culture. In the absence of modulators, vinblastine accumulated in tissues to different extents— Howest in brain, highest in pancreas and intestine. The extent of accumulation was directly proportional to the vinblastine dose in the range 0.2–6 mg/kg body weight. Both at high and low vinblastine doses, all the modulators except quinidine increased the ability of liver, kidney, intestine and lung to accumulate vinblastine by up to 5-fold, and with the further exception of mefloquine, also increased vinblastine levels in pancreas. Only dipyrida-mole had a marked effect also in brain. Cyclosporin A provided effective increases in the tissue distribution of vinblastine at plasma concentrations similar to those needed to block the multidrug pump in the case of cells in cell culture. For mefloquine, plasma concentrations three or four times higher were needed in vivo than were found to be effective in cell culture. The mouse system provides a quick and rellable in vivo method to assay modulators before they are tested in the clinic.