Drug–drug interaction mediated by inhibition and induction of P-glycoprotein

Abstract

P-glycoprotein (P-gp), the most extensively studied ATP-binding cassette transporter, functions as a biological barrier by extruding toxic substances and xenobiotics out of cells. In vitro and in vivo studies have demonstrated that P-gp plays a significant role in drug absorption and disposition. Like cytochrome P450 enzymes, inhibition and induction of P-gp have been reported as the causes of drug–drug interactions. Because many prototypic inhibitors and inducers affect both CYP3A4 and P-gp, many drug interactions caused by these inhibitors and inducers involve these two systems. Clinically, it is very difficult to quantitatively differentiate P-gp-mediated drug interactions versus CYP3A4-mediated drug interactions, unless their relative contributions can be accurately estimated. Therefore, care should be exercised when interpreting drug interaction data and exploring the underlying mechanisms of drug interactions.

Introduction

P-glycoprotein (P-gp), the first known ATP binding cassette transporter, is composed of two homologous and symmetrical cassettes; each contains six transmembrane domains that are separated by an intracellular flexible linker polypeptide loop with an ATP-binding motif [1]. Site-directed mutagenesis and antibody mapping studies suggest that the two cassettes of P-gp interact cooperatively to form a single functional unit [2], [3]. In humans, two members of the P-gp gene family (MDR1 and MDR3) exist, while three members of this family (mdr1a, mdr1b and mdr2) are found in mice [1]. The P-gp encoded by human MDR1 and mouse mdr1a/1b genes functions as a drug efflux transporter by extruding drugs out of cells, while human MDR3 P-gp and mouse mdr2 P-gp are believed to be functional in phospholipid transport [4], [5].

The human MDR1 P-gp is localized on the canalicular surface of hepatocytes, the apical surface of renal tubular epithelial cells, the apical surface of epithelial cells in intestine and placenta, and the luminal surface of capillary endothelial cells in the brain [6], [7]. The anatomical localization of P-gp suggests that P-gp may play an important role in the processes of absorption, distribution, metabolism, and excretion of drugs in humans. While the physiological function of P-gp is still not fully understood, P-gp is able to extrude a wide variety of structurally and chemically unrelated compounds out of cells. Because of its broad substrate specificity, drug interactions may occur when P-gp substrates and inhibitors (or inducers) are coadministered. Indeed, inhibition and induction of P-gp have been reported in animals and humans as the causes of drug–drug interaction.

The main purpose of this article is to discuss the potential for P-gp-mediated interactions and its clinical implications. In addition, the role of P-gp in drug absorption, distribution, metabolism, and excretion will also be reviewed.