Dai HaiQing, Marbach Peter, Lemaire Michel, Hayes Michael, Elmquist William F
Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455, USA.
J Pharmacol Exp Ther. 2003 Mar;304(3):1085-92. doi: 10.1124/jpet.102.045260.
The adequate distribution of STI-571 (Gleevec) to the central nervous system (CNS) is critical for its effective use in CNS tumors. P-glycoprotein-mediated efflux in the blood-brain barrier may play a role in the CNS delivery of this drug. Whether STI-571 is a substrate of P-glycoprotein was determined by examining the directional flux of [(14)C]STI-571 in parental and MDR1-transfected Madin-Darby canine kidney (MDCK) II epithelial cell monolayers. The basolateral-to-apical flux of STI-571 was 39-fold greater than the apical-to-basolateral flux in the MDR1-transfected cells and 8-fold greater in the parental cell monolayers. This difference in directional flux was significantly reduced by a specific P-glycoprotein inhibitor (2R)-anti-5-[3-[4-(10,11-difluoromethanodibenzo-suber-5-yl)piperazin-1-yl]-2-hydroxypropoxy]quinoline trihydrochloride (LY335979). The role of P-glycoprotein in the CNS distribution of STI-571 was examined in vivo, using wild-type and mdr1a/b (-/-) knockout mice that were orally administered 25 mg/kg [(14)C]STI-571. In the wild-type mice, the brain-to-plasma STI-571 concentration ratio at all time points was low (1-3%); however, there was an 11-fold greater brain partitioning of STI-571 at 1 h postdose in the mdr1a/b (-/-) mice compared with the wild-type mice. When 12.5 mg/kg STI-571 was given intravenously, the brain-to-plasma ratio of STI-571 in the mdr1a/b (-/-) mice was approximately 7-fold greater than that of wild-type mice up to 120 min postdose. These data indicate that STI-571 is a substrate of P-glycoprotein, and that the inhibition of P-glycoprotein affects the transport of STI-571 across MDCKII monolayers. Moreover, P-glycoprotein plays an important role in limiting the distribution of STI-571 to the CNS.
STI-571（格列卫）在中枢神经系统（CNS）中的充分分布对其在中枢神经系统肿瘤中的有效应用至关重要。血脑屏障中P-糖蛋白介导的外排可能在该药物的中枢神经系统递送中起作用。通过检测[(14)C]STI-571在亲本和MDR1转染的Madin-Darby犬肾（MDCK）II上皮细胞单层中的定向通量，确定STI-571是否为P-糖蛋白的底物。在MDR1转染的细胞中，STI-571从基底外侧到顶端的通量比从顶端到基底外侧的通量高39倍，在亲本细胞单层中高8倍。一种特异性P-糖蛋白抑制剂（2R）-反式-5-[3-[4-(10,11-二氟亚甲基二苯并环庚-5-基)哌嗪-1-基]-2-羟基丙氧基]喹啉三盐酸盐（LY335979）可显著降低这种定向通量的差异。利用口服给予25mg/kg[(14)C]STI-571的野生型和mdr1a/b(-/-)基因敲除小鼠，在体内研究了P-糖蛋白在STI-571中枢神经系统分布中的作用。在野生型小鼠中，所有时间点的脑-血浆STI-571浓度比都很低（1%-3%）；然而，与野生型小鼠相比，mdr1a/b(-/-)小鼠在给药后1小时时STI-571的脑内分配量高11倍。当静脉注射12.5mg/kg STI-571时，在给药后长达120分钟内，mdr1a/b(-/-)小鼠中STI-571的脑-血浆比约比野生型小鼠高7倍。这些数据表明STI-571是P-糖蛋白的底物，并且P-糖蛋白的抑制会影响STI-571跨MDCKII单层的转运。此外，P-糖蛋白在限制STI-571向中枢神经系统的分布中起重要作用。
