Schinkel A H, Wagenaar E, van Deemter L, Mol C A, Borst P
The Netherlands Cancer Institute, Division of Molecular Biology, Amsterdam, The Netherlands.
J Clin Invest. 1995 Oct;96(4):1698-705. doi: 10.1172/JCI118214.
We have previously shown that absence of the mouse mdr1a (also called mdr3) P-glycoprotein in mdr1a (-/-) "knockout" mice has a profound effect on the tissue distribution and elimination of vinblastine and ivermectin, and hence on the toxicity of these compounds. We show here that the mouse mdr1a and the human MDR1 P-glycoprotein actively transport ivermectin, dexamethasone, digoxin, and cyclosporin A and, to a lesser extent, morphine across a polarized kidney epithelial cell layer in vitro. Injection of these radio-labeled drugs in mdr1a (-/-) and wild-type mice resulted in markedly (20- to 50-fold) higher levels of radioactivity in mdr1a (-/-) brain for digoxin and cyclosporin A, with more moderate effects for dexamethasone (2- to 3-fold) and morphine (1.7-fold). Digoxin and cyclosporin A were also more slowly eliminated from mdr1a (-/-) mice. Our findings show that P-glycoprotein can be a major determinant for the pharmacology of several medically important drugs other than anti-cancer agents, especially in the blood-brain barrier. These results may explain a range of pharmacological interactions observed between various drugs in patients.
我们先前已经表明，mdr1a（也称为mdr3）基因敲除小鼠缺乏小鼠P-糖蛋白，这对长春碱和伊维菌素的组织分布和消除有深远影响，进而对这些化合物的毒性产生影响。我们在此表明，小鼠mdr1a和人类MDR1 P-糖蛋白在体外能主动转运伊维菌素、地塞米松、地高辛和环孢素A，在较小程度上还能转运吗啡穿过极化的肾上皮细胞层。给mdr1a基因敲除小鼠和野生型小鼠注射这些放射性标记药物后，地高辛和环孢素A在mdr1a基因敲除小鼠大脑中的放射性水平显著升高（20至50倍），地塞米松（2至3倍）和吗啡（1.7倍）的影响则较为温和。地高辛和环孢素A从mdr1a基因敲除小鼠体内的消除也更慢。我们的研究结果表明，P-糖蛋白可能是除抗癌药物外几种医学上重要药物药理学的主要决定因素，尤其是在血脑屏障方面。这些结果可能解释了患者中各种药物之间观察到的一系列药理相互作用。
