Watt G, Long G W, Grogl M, Martin S K
Department of Hematology, Walter Reed Army Institute of Research, Washington, DC.
Trans R Soc Trop Med Hyg. 1990 Mar-Apr;84(2):187-90. doi: 10.1016/0035-9203(90)90248-d.
Agents capable of reversing multidrug resistance (mdr) in falciparum malaria were investigated for potentiation of chloroquine accumulation and toxicity in a cell culture system. Verapamil, its analog RO11-2933, and desipramine caused a dose-dependent increase in the accumulation of chloroquine (CQ) within human and mouse hepatocytes but not human lung cells. Only those cells in which drug accumulation was enhanced by reversing agents reacted positively for P-glycoprotein (PgP)--the putative mediator of the enhanced drug efflux characteristic of mdr. Clinically achievable concentrations of verapamil (0.4 microM) and desipramine (1 microM) increased CQ accumulation within primary mouse hepatocytes by more than 50%. A well-differentiated normal human cell line (Hep-G2) was killed in media containing a combination of supraphysiological concentrations of CQ and verapamil but survived the same concentrations of either drug alone. Reversing agents may block PgP-mediated drug export from normal tissues as well as from MDR cells. Iatrogenic toxicity resulting from this accumulation of potentially toxic drugs such as CQ within normal cells could complicate the reversal of mdr in vivo.
在细胞培养系统中，研究了能够逆转恶性疟原虫多药耐药性（mdr）的药物对氯喹蓄积和毒性的增强作用。维拉帕米、其类似物RO11 - 2933和地昔帕明可使氯喹（CQ）在人及小鼠肝细胞内的蓄积呈剂量依赖性增加，但对人肺细胞无此作用。只有那些蓄积药物因逆转剂而增加的细胞对P - 糖蛋白（PgP）呈阳性反应，PgP被认为是mdr增强药物外排特性的介质。临床可达到的维拉帕米浓度（0.4 microM）和地昔帕明浓度（1 microM）可使原代小鼠肝细胞内的CQ蓄积增加超过50%。一种高度分化的正常人细胞系（Hep - G2）在含有超生理浓度CQ和维拉帕米组合的培养基中死亡，但单独使用相同浓度的任何一种药物时均可存活。逆转剂可能会阻断PgP介导的药物从正常组织以及多药耐药细胞中的输出。正常细胞内这种潜在有毒药物如CQ的蓄积所导致的医源性毒性可能会使体内mdr的逆转复杂化。
