Kinetic parameters for reversal of the multidrug pump as measured for drug accumulation and cell killing
Kinetic parameters for reversal of the multidrug pump as measured for drug accumulation and cell killing
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DOI：
10.1007/s002800050468
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发表时间：
1996-06-01
影响因子：
3
通讯作者：
Stein, WD
中科院分区：
文献类型：
--
作者：
Lan, LB;Ayesh, S;Stein, WD
我们确定的动力学参数，描述了20种不同的调节剂的多药耐药泵逆转的细胞毒素积累的耐药株P388白血病细胞（P388/ADR），并对这些细胞的细胞杀伤逆转的影响。当通过直接比较相关方案（蓄积或细胞杀伤）的幅度进行测量时，蓄积逆转的Ki通常比细胞毒性降低的Ki大4或5倍。我们表明，这只是一个明显的差异，因为两个协议的完整的理论分析允许获得的内在K-i的两个程序，这些计算的K-i值几乎是相同的。我们发现，对于研究的六种调节剂（即环孢菌素A、奎尼丁、双嘧达莫、普罗帕酮、甲氟喹、他莫昔芬），在从文献中挑选的耐受血浆水平下，泵逆转的程度应优于90%。
We determined the kinetic parameters that describe the effect of 20 different modulators of the multidrug resistance pump on the reversal of cytotoxin accumulation in a resistant strain of P388 leukemia cells (P388/ADR), and on the reversal of cell killing for these cells. When measured by a direct comparison of the amplitude of the pertinent protocol (accumulation or cell killing), the K-i for reversal of accumulation was generally some four or five times larger than that for reduction of cytotoxicity. We showed that this was only an apparent discrepancy, since a full theoretical analysis of the two protocols allowed the intrinsic K-i to be obtained for the two procedures and these computed K-i values were then almost identical. We found that for six of the modulators studied (namely, cyclosporin A, quinidine, dipyridamole, propafenone, mefloquine, tamoxifen) the extent of pump reversal should be better than 90% at tolerated plasma levels culled from the literature.