P-glycoprotein ABCB1: a major player in drug handling by mammals

Abstract

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.

Figure 1. Overview of ABCB1 functional expression throughout the body.

Blue lines indicate the location of ABCB1. Small arrows indicate the direction of ABCB1-mediated transport. Bold green arrows indicate net body excretion of ABCB1 substrates. ABCB1 in the BBB and blood-testis and placental fetal-maternal barrier protects brain, testis, and fetus, respectively, from accumulation of ABCB1 substrates. ABCB1 in small and large intestine reduces intestinal uptake (oral availability) and mediates direct intestinal excretion of substrates. ABCB1 in liver and kidney mediates hepatobiliary and renal excretion of substrates. ABCB1 expression in tumor cells can contribute to multidrug resistance.