Pharmacologie Cellulaire et moléculaire, Louvain Drug Research Institute, Université Catholique de Louvain, B- 1200 Brussels, Belgium.
Curr Drug Targets. 2011 May;12(5):600-20. doi: 10.2174/138945011795378504.
Nine proteins of the ABC superfamily (P-glycoprotein, 7 MRPs and BCRP) are involved in multidrug transport. Being localised at the surface of endothelial or epithelial cells, they expel drugs back to the external medium (if located at the apical side [P-glycoprotein, BCRP, MRP2, MRP4 in the kidney]) or to the blood (if located at the basolateral side [MRP1, MRP3, MRP4, MRP5]), modulating thereby their absorption, distribution, and elimination. In the CNS, most transporters are oriented to expel drugs to the blood. Transporters also cooperate with Phase I/Phase II metabolism enzymes by eliminating drug metabolites. Their major features are (i) their capacity to recognize drugs belonging to unrelated pharmacological classes, and (ii) their redundancy, a single molecule being possibly substrate for different transporters. This ensures an efficient protection of the body against invasion by xenobiotics. Competition for transport is now characterized as a mechanism of interaction between co-administered drugs, one molecule limiting the transport of the other, potentially affecting bioavailability, distribution, and/or elimination. Again, this mechanism reinforces drug interactions mediated by cytochrome P450 inhibition, as many substrates of P-glycoprotein and CYP3A4 are common. Induction of the expression of genes coding for MDR transporters is another mechanism of drug interaction, which could affect all drug substrates of the up-regulated transporter. Overexpression of MDR transporters confers resistance to anticancer agents and other therapies. All together, these data justify why studying drug active transport should be part of the evaluation of new drugs, as recently recommended by the FDA.
ABC 超家族的 9 种蛋白（P-糖蛋白、7 种 MRP 和 BCRP）参与多药转运。这些蛋白位于内皮或上皮细胞表面，将药物排出至外环境（如果位于顶端侧[P-糖蛋白、BCRP、MRP2、MRP4 在肾脏]）或血液（如果位于基底外侧[MRP1、MRP3、MRP4、MRP5]），从而调节药物的吸收、分布和消除。在中枢神经系统中，大多数转运体倾向于将药物排出至血液。转运体还通过消除药物代谢物与 I 相/II 相代谢酶合作。它们的主要特征是（i）识别属于不同药理类别的药物的能力，以及（ii）其冗余性，即单个分子可能是不同转运体的底物。这确保了身体对异生物质入侵的有效保护。药物竞争转运现在被认为是共同给予的药物之间相互作用的机制之一，一种分子限制另一种分子的转运，可能会影响生物利用度、分布和/或消除。同样，这种机制加强了由细胞色素 P450 抑制介导的药物相互作用，因为 P-糖蛋白和 CYP3A4 的许多底物是共同的。MDR 转运体的基因表达诱导是另一种药物相互作用机制，可能会影响上调转运体的所有药物底物。MDR 转运体的过度表达赋予了对抗癌药物和其他治疗方法的耐药性。所有这些数据都证明了为什么研究药物主动转运应该成为新药物评估的一部分，正如 FDA 最近所建议的那样。
