J Clin Invest. 2013 Oct;123(10):4131-3. doi: 10.1172/JCI70430. Epub 2013 Oct 1.
Mammalian P-glycoproteins are active drug efflux transporters located in the plasma membrane. In the early nineties, we generated knockouts of the three P-glycoprotein genes of mice, the Mdr1a, Mdr1b, and Mdr2 P-glycoproteins, now known as Abcb1a, Abcb1b, and Abcb4, respectively. In the JCI papers that are the subject of this Hindsight, we showed that loss of Mdr1a (Abcb1a) had a profound effect on the tissue distribution and especially the brain accumulation of a range of drugs frequently used in humans, including dexamethasone, digoxin, cyclosporin A, ondansetron, domperidone, and loperamide. All drugs were shown to be excellent substrates of the murine ABCB1A P-glycoprotein and its human counterpart, the MDR1 P-glycoprotein, ABCB1. We found that the ability of ABCB1 to prevent accumulation of some drugs in the brain is a prerequisite for their clinical use, as absence of the transporter led to severe toxicity or undesired CNS pharmacodynamic effects. Subsequent work has fully confirmed the profound effect of the drug-transporting ABCB1 P-glycoprotein on the pharmacokinetics of drugs in humans. In fact, every new drug is now screened for transport by ABCB1, as this limits oral availability and penetration into sanctuaries protected by ABCB1, such as the brain.
哺乳动物 P-糖蛋白是位于质膜上的活性药物外排转运蛋白。在 90 年代初期，我们敲除了小鼠的三个 P-糖蛋白基因，即 Mdr1a、Mdr1b 和 Mdr2 P-糖蛋白，它们现在分别被称为 Abcb1a、Abcb1b 和 Abcb4。在作为本文 Hindsight 主题的 JCI 论文中，我们表明 Mdr1a（Abcb1a）的缺失对一系列在人类中经常使用的药物的组织分布，尤其是脑内积累，产生了深远的影响，这些药物包括地塞米松、洋地黄毒苷、环孢素 A、昂丹司琼、多潘立酮和洛哌丁胺。所有这些药物都被证明是鼠源性 ABCB1A P-糖蛋白及其人源对应物 MDR1 P-糖蛋白 ABCB1 的良好底物。我们发现 ABCB1 防止某些药物在脑内积累的能力是其临床应用的前提，因为缺乏该转运体导致严重的毒性或不期望的中枢神经系统药效学效应。随后的工作充分证实了药物转运 ABCB1 P-糖蛋白对人类药物药代动力学的深远影响。事实上，现在每一种新药都要进行 ABCB1 转运筛选，因为这限制了药物的口服可用性和穿透 ABCB1 保护的避难所，如大脑。
